Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof

ABSTRACT

The present invention relates to compounds of general formula (I) 
     
       
         
         
             
             
         
       
     
     and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, and the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.

1. FIELD OF THE INVENTION

The present invention relates to compounds of general formula (I)

and the tautomers and the salts thereof, particularly thepharmaceutically acceptable salts thereof with inorganic or organicacids and bases, which have valuable pharmacological properties,particularly an inhibitory effect on epithelial sodium channels, the usethereof for the treatment of diseases, particularly diseases of thelungs and airways.

2. BACKGROUND TO THE INVENTION

Amiloride type compounds are known from the prior art as activesubstances for example for the treatment of diseases of the lungs andairways (J. Med. Chem. 49 (2006) 4098-4115). WO 08135557 disclosescompounds of similar structure showing ENaC (Epithelial Sodium Channel)inhibitor activity.

The problem of the present invention is to prepare new compounds whichmay be used therapeutically for the treatment of pathophysiologicalprocesses treatable by the blockade of an epithelial sodium channel,particularly for the treatment of the lungs and airways.

3. DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that the problem mentioned above issolved by compounds of formula (I) and (IC) of the present invention.

The present invention therefore relates to a compound of formula (I)

wherein

-   -   A denotes a bond or is selected from the group consisting of O,        —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂—O—, —CH₂—NR^(A1)— and        —NR^(A1)—, preferably bond, —CH₂— and —CH₂CH₂—,        -   wherein        -   R^(A1) denotes hydrogen or C₁₋₆-alkyl, preferably hydrogen            or C₁₋₂-alkyl,    -   B denotes        -   —CH₂— or —CH₂CH₂—, preferably —CH₂—, or        -   provided that A is not O or —NR^(A1), B denotes a bond    -   D, E denote independently from each other a bond or —CH₂—,        preferably —CH₂—,    -   F denotes optionally substituted aryl, preferably phenyl,        preferably substituted by R², R³, R⁴, R⁶, R⁷, R^(2a), R^(3a),        R^(4a), R^(6a) or R^(7a),        -   or optionally substituted heteroaryl, preferably thiophenyl,            pyridyl, pyrimidinyl or pyridonyl, preferably substituted by            R², R³, R⁴, R⁶, R⁷, R^(2a), R^(3a), R^(4a), R^(6a) or            R^(7a).        -   F most preferably denotes phenyl, 4-halo-phenyl,            particularly preferred phenyl,    -   G denotes a group of formula (g.1), (g.2) or (g.3)

-   -   R¹ is selected from the group consisting of        -   hydrogen, C₁₋₆alkyl, optionally substituted piperidinyl-CO—,            optionally substituted piperazinyl-CO—, optionally            substituted piperidinyl-NH—CO—, R^(1.1)—SO₂—,            R^(1.2)—C₂₋₄-alkyl-NH—CO—, H₃C—NH—CO—,            R^(1.2.4)—O—CO—CH₂—NH—CO—,            R^(1.2)—C₂₋₄alkyl-N(C₁₋₄-alkyl)-CO—, H₃C—N(C₁₋₄-alkyl)-CO—,            R^(1.2.4)—O—CO—CH₂—N(C₁₋₄-alkyl)-CO—,            R^(1.3)—C₁₋₆-alkyl-CO—, R^(1.4)—C₂₋₆-alkyl-, optionally            substituted phenyl-CH₂—, R^(1.4.3)—O—CO—CH₂—, HO—CO—CH₂— and            HO—SO₂—CH₂—,        -   R^(1.5)—C₁₋₆-alkyl-CO— and R^(1.6)—C(NH)—,        -   wherein        -   R^(1.1) is selected from the group consisting of            C₁₋₄-alkyl-, H₂NC(NH)NH—C₁₋₆-alkyl-,            R^(1.2.1)R^(1.2.2)N—C₁₋₄-alkyl-,            R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—C₁₋₄-alkyl, HOCO—C₁₋₄-alkyl-            and C₁₋₃-alkyl-OCO—C₁₋₄-alkyl-,        -   R^(1.2) is selected from the group consisting of hydrogen,            H₂NC(NH)NH—, R^(1.2.1)R^(1.2.2)N—,            R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—,            R^(1.2.3)—HN—C(NR^(1.23))—NH—, R^(1.2.4)—O—CO—,            R^(1.2.5)—O—CO—NH— and HO—CO—, HOSO₂—, preferably            R^(1.2.1)R^(1.2.2)N—, R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—,            R^(1.2.3)—HN—C(NR^(1.2.3))—NH—            -   wherein            -   R^(1.2.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.2.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   or            -   R^(1.2.1) and R^(1.2.2) together build a 4- to                7-membered hetercyclic ring containing one N-atom,                preferably a 6- or 5-membered heterocyclic ring            -   R^(1.2.3) denotes C₁₋₆-alkyl, preferably C₁₋₄-alkyl,            -   R^(1.2.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.2.5) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,        -   R^(1.3) is selected from the group consisting of hydrogen,            C₁₋₆-alkyl, C₁₋₆-alkyl-O—, optionally substituted phenyl,            R^(1.3.1)R^(1.3.2)N—, R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—,            R^(1.2.3)—HN—C(NR^(1.2.3))—NH—, H₂NC(NH)NH—, R^(1.2.4)—O—CO,            HO—CO— and HOSO₂—,            -   wherein            -   R^(1.3.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.3.2) denotes hydrogen or C₁₋₆-alkyl,            -   or            -   R^(1.3.1) and R^(1.3.2) together form a 4- to 7-membered                hetercyclic ring containing one N-atom, preferably a                6-membered heterocyclic ring containing one N-atom,            -   preferably hydrogen or C₁₋₄-alkyl,        -   R^(1.4) is selected from the group consisting of hydrogen,            R^(1.4.1)R^(1.4.2)N—, R^(1.4.1)R^(1.4.2)R^(1.4.3)N⁺—,            H₂N—C(NH)—NH—, R^(1.4.3)—HN—C(NR^(1.4.4))—NH, optionally            substituted phenyl, R^(1.4.3)—O—CO—, R^(1.4.4)—O—CO—NH—,            HO—CO— and HOSO₂—,            -   wherein            -   R^(1.4.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.3) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.4.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,        -   R^(1.5) is selected from the group consisting of hydrogen,            C₁₋₆-alkyl-O—, R^(1.5.1)R^(1.5.2)N—,            R^(1.5.1)R^(1.5.2)R^(1.5.3)N⁺—, H₂N—C(NH)—NH—, optionally            substituted phenyl, R^(1.5.3)—O—CO—, R^(1.5.4)—O—CO—NH—,            HO—CO—, HOSO₂—,            -   wherein            -   R^(1.5.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.5.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.5.3) denotes hydrogen or C₁₋₆-alkyl preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.5.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,        -   R^(1.6) denotes R^(1.6.1)R^(1.6.2)N—,            -   wherein            -   R^(1.6.1) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or methyl,            -   R^(1.6.2) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or methyl,    -   R^(1b) is selected from the group consisting of C₁₋₄-alkyl,        -   R^(1.4)—C₂₋₆-alkyl-, optionally substituted phenyl-CH₂—,            R^(1.4.3)—O—CO—CH₂— and HO—CO—CH₂—, preferably C₁₋₄-alkyl,            particularly preferred methyl,        -   wherein        -   R^(1.4) is selected from the group consisting of hydrogen,            R^(1.4.1)R^(1.4.2)N—, R^(1.4.1)R^(1.4.2)R^(1.43)N⁺—,            H₂N—C(NH)—NH—, R^(1.4.3)—HN—C(NR^(1.4.4))—NH, optionally            substituted phenyl, R^(1.4.3)—O—CO—, R^(1.4.4)—O—CO—NH—,            HO—CO— and HOSO₂—,            -   wherein            -   R^(1.4.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.3) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.4.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,    -   R^(1s) denotes C₁₋₆-alkyl, preferably methyl,    -   X⁻ denotes any anion forming a pharmaceutically acceptable salt,        preferably selected from among CF₃—COO⁻, Cl⁻, I⁻, Br⁻, HCOO⁻ and        CH₃—COO⁻, most preferably Cl⁻ and CF₃—COO⁻,    -   L denotes a bridging group —CO—NH—C₂₋₆-alkyl-NH—CO—,        —COC₁₋₆-alkyl-CO—, or —C₂₋₆-alkyl-,        -   forming a compound of formula (IC),        -   whereby the molecular entities of formula (IC) connected by            L may be identical or different

-   -   R⁵ denotes Cl or Br, preferably Cl,

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, optionally in form of thehydrates, solvates or prodrugs thereof and optionally thepharmacologically acceptable acid addition salts thereof.

Preferred compounds of formula (IA), (IB) or (IC.1) are those wherein

-   -   A denotes a bond, —CH₂—, —CH₂CH₂— or CH₂—O—, preferably        —CH₂CH₂—,    -   R¹ is selected from the group consisting of        -   hydrogen, C₁₋₆alkyl, R^(1.1)—SO₂—,            R^(1.2)—C₂₋₄-alkyl-NH—CO—, H₃C—NH—CO—,            R^(1.2.4)—O—CO—CH₂—NH—CO—,            R^(1.2)—C₂₋₄-alkyl-N(C₁₋₄-alkyl)-CO—, H₃C—N(C₁₋₄-alkyl)-CO—,            R^(1.2.4)—O—CO—CH₂—N(C₁₋₄-alkyl)-CO—,            R^(1.3)—C₁₋₆-alkyl-CO—, R^(1.4)—C₂₋₆-alkyl-, optionally            substituted phenyl-CH₂—, R^(1.4.3)—O—CO—CH₂—, HO—CO—CH₂— and            HOSO₂—CH₂—, R^(1.5)—C₁₋₆-alkyl-CO— and R^(1.6)—C(NH)—,        -   wherein        -   R^(1.1) denotes C₁₋₄-alkyl-;        -   R^(1.2) is selected from the group consisting of            -   hydrogen, R^(1.2.1)R^(1.2.2)N—,                R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—, R^(1.2.4)—O—CO—, HO—CO—                and R^(1.2.5)—O—CO—NH—,            -   wherein            -   R^(1.2.1) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.2.2) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.2.3) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.2.4) denotes C₁₋₆-alkyl; preferably C₁₋₄-alkyl,            -   R^(1.2.5) denotes C₁₋₆-alkyl; preferably C₁₋₄-alkyl,        -   R^(1.3) is selected from the group consisting of hydrogen,            C₁₋₆-alkyl, C₁₋₆-alkyl-O—, and optionally substituted phenyl        -   R^(1.4) is selected from the group consisting of hydrogen,            R^(1.4.1)R^(1.4.2)N—, R^(1.4.1)R^(1.4.2)R^(1.4.3)N⁺—,            H₂N—C(NH)—NH—, R^(1.4.3)—HN—C(NR^(1.4.4))—NH—, optionally            substituted phenyl, R^(1.4.3)—O—CO—, R^(1.4.4)—O—CO—NH—,            HO—CO— and HOSO₂—,            -   wherein            -   R^(1.4.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.3) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.4.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,        -   R^(1.5) is selected from the group consisting of hydrogen,            C₁₋₆-alkyl-O—, R^(1.5.1)R^(1.5.2)N—,            R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—, H₂N—C(NH)—NH—,            R^(1.5.3)—O—CO—, R^(1.5.4)—O—CO—NH—, optionally substituted            phenyl,            -   wherein            -   R^(1.5.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.5.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.5.3) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.5.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,        -   R^(1.6) denotes R^(1.6.1)R^(1.6.2)N—,            -   wherein            -   R^(1.6.1) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or methyl,            -   R^(1.6.2) denotes hydrogen or C₁₋₆-alkyl; preferably                hydrogen or methyl,    -   R^(1b) denotes C₁₋₄-alkyl, preferably methyl,    -   R^(1s) denotes C₁₋₆-alkyl, preferably methyl,    -   X⁻ denotes any anion forming a pharmaceutically acceptable salt,        preferably selected from among CF₃—COO⁻, Cl⁻, I⁻, Br⁻, HCOO⁻ and        CH₃—COO⁻, most preferably Cl⁻ and CF₃—COO⁻,    -   L denotes a bridging group —CO—NH—C₂₋₆-alkyl-NH—CO—,        —COC₁₋₆-alkyl-CO— or —C₂₋₆-alkyl-,        -   forming a compound of formula (IC.1),        -   whereby the molecular entities of formula (IC.1) connected            by L may be identical or different

-   -   R², R³, R⁴, R⁶, R⁷, R^(2a), R^(3a), R^(4a), R^(6a), R^(7a)        independently from each other are selected from the group        consisting of hydrogen, halogen, CN, C₁₋₄alkyl, C₁₋₃-alkyl-O—,        C₁₋₃-alkyl-OCO—, —COOR^(4.1), —CONR^(4.2)R^(4.3) and —OR^(4.1),        preferably hydrogen,        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl        -   or        -   R³ and R⁴ or R^(3a) and R^(4a) together denote            —O—C₁₋₃-alkyl-O—;        -   preferably —O—C₁₋₂-alkyl-O—,

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, optionally in form of thehydrates, solvates or prodrugs thereof and optionally thepharmacologically acceptable acid addition salts thereof.

Particularly preferred are compounds of formula (IA), wherein

-   -   A denotes a bond, —CH₂— or —CH₂CH₂—,    -   R¹ is selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₄-alkyl-SO₂—, C₁₋₄-alkyl-NH—CO—,            H₂N—CO—, H₂N—C₁₋₄-alkyl-, H₂N—C₁₋₄-alkyl-CO—,            H₂N—C₁₋₄-alkyl-NH—CO—, Phenyl-CO—, Phenyl-CH₂—CO—,            Phenyl-CH₂—, C₁₋₆-alkyl-CO—, C₁₋₆-alkyl-O—C₁₋₄-alkyl-CO—,            (CH₃)₂N—C₁₋₄-alkyl-, (CH₃)₂N—C₁₋₄-alkyl-NH—CO—,            (CH₃)₃N⁺—C₁₋₄-alkyl-NH—CO—, (CH₃)₃N⁺—C₁₋₄-alkyl-CO—,            (CH₃)₃N⁺—C₂₋₄-alkyl-, (CH₃)N⁺—C₁₋₄-alkyl-N(C₁₋₄-alkyl)-CO—,            H₂N—C(NH)—NH—C₁₋₆—NH—CO—, C₁₋₆-alkyl-O—CO—,            C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-, C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-CO—,            C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-NH—CO—,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-CO—,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-NH—CO—, HOCO—C₁₋₄-alkyl-,            HOCO—C₁₋₄-alkyl-CO—, HOCO—C₁₋₄-alkyl-NH—CO—, H₂N—CNH— and            H₂NC(NH)NH—C₁₋₆-alkyl-CO—,    -   R² independently from each other are selected from the group        consisting of hydrogen, halogen, CN, C₁₋₄-alkyl and C₁-alkyl-O—,    -   R⁶ independently from each other are selected from the group        consisting of hydrogen, halogen, CN, C₁₋₄-alkyl and C₁-alkyl-O—    -   R³ are selected from the group consisting of hydrogen, halogen,        CN and C₁₋₄-alkyl,    -   R⁴ independently from each other are selected from the group        consisting of hydrogen, halogen, CN, C₁₋₄-alkyl,        C₁₋₄-alkyl-OCO—, —COOR^(4.1) and —CONR^(4.2)R^(4.3),        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or methyl;        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or methyl;        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or methyl;    -   or    -   R³ and R⁴ together denote —O—C₁₋₃-alkyl-O—; preferably        —O—C₁₋₂-alkyl-O—;

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

Also particularly preferred are compounds of formula (IC.1) wherein

-   -   A denotes a bond, —CH₂— or —CH₂CH₂—,    -   L denotes a bridging group —CO—NH—C₂₋₆-alkyl-NH—CO—,        -   forming a compound of formula IC or IC.1,    -   R², R^(2a) independently from each other are selected from the        group consisting of hydrogen, halogen, CN, C₁₋₄-alkyl and        C₁-alkyl-O—,    -   R⁶, R^(6a) independently from each other are selected from the        group consisting of hydrogen, halogen, CN, C₁₋₄-alkyl and        C₁-alkyl-O—    -   R³, R^(3a) are selected from the group consisting of hydrogen        halogen, CN and C₁₋₄-alkyl,    -   R⁴, R^(4a) independently from each other are selected from the        group consisting of hydrogen halogen, CN, C₁₋₄-alkyl,        C₁₋₄-alkyl-OCO—, —COOR^(4.1) and —CONR^(4.2)R^(4.3),        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or methyl;        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or methyl;        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or methyl;    -   or    -   R³ and R⁴ or R^(3a) and R^(4a) together denote —O—C₁₋₃-alkyl-O—;        preferably O—C₁₋₂-alkyl-O—;

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

Also particularly preferred are compounds of formula (IB) wherein

-   -   R^(1b) denotes C₁₋₄-alkyl, preferrably methyl,    -   and    -   R^(1a) denotes C₁₋₆-alkyl, preferably methyl,

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, optionally in form of thehydrates, solvates or prodrugs thereof and optionally thepharmacologically acceptable acid addition salts thereof.

Also particularly preferred are compounds of formula (IC) wherein

-   -   L denotes a bridging group —CO—NH—C₂₋₆-alkyl-NH—CO—,        -   forming a compound of formula (IC) or (IC.1),

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, optionally in form of thehydrates, solvates or prodrugs thereof and optionally thepharmacologically acceptable acid addition salts thereof.

Especially preferred are compounds of formula (IA), (IB) or (IC.1),wherein

-   -   R², R³, R⁴, R⁶ and R⁷ denote hydrogen.

Also especially preferred are compounds of formula (IA), (IB) or (IC.1),wherein

-   -   R², R³, R⁴, R⁶, R⁷, R^(2a), R^(3a), R^(4a), R^(6a) and R^(7a)        denote hydrogen.

Also especially preferred are compounds of formula (IA), (IB) or (IC),wherein

-   -   A denotes —CH₂CH₂—, and    -   E, D denote —CH₂—

A further embodiment of the current invention are compounds of formula(I), (IA), (IB) or (IC) or a pharmaceutically acceptable salt thereof asa medicament, preferably compounds of formula (IA), (IB) or (IC)

A further embodiment of the current invention are compounds of formula(I), (IA), (IB) or (IC), preferably compounds of formula (IA), (IB) or(IC), or a pharmaceutically acceptable salt thereof for the treatment ofrespiratory diseases or complaints, and allergic diseases of theairways.

Preferred are compounds of formula (I) or (IC), preferably compounds offormula (IA), (IB) or (IC), or a pharmaceutically acceptable saltthereof for the treatment of a disease selected from among chronicbronchitis, acute bronchitis, bronchitis caused by bacterial or viralinfection or fungi or helminths, allergic bronchitis, toxic bronchitis,chronic obstructive pulmonary disease (COPD), asthma (intrinsic orallergic), pediatric asthma, bronchiectasis, allergic alveolitis,allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis ormucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonaryemphysema, interstitial lung diseases, alveolitis, hyperreactiveairways, nasal polyps, pulmonary oedema, pneumonitis of differentorigins, e.g. radiation-induced or caused by aspiration or infectiouspneumonitis, preferably chronic bronchitis, acute bronchitis,bronchitis, chronic obstructive pulmonary disease (COPD), asthma(intrinsic or allergic), cystic fibrosis and pediatric asthma,preferably chronic bronchitis, COPD and cystic fibrosis.

A pharmaceutical composition comprising at least one compound accordingto the invention or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

A further embodiment of the current invention is medicament combinationswhich contain, besides one or more compounds according to the invention,as further active substances, one or more compounds selected from amongthe categories of further ENaC inhibitors, betamimetics,anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists,EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists,MAP-kinase inhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors,and cystic fibrosis transmembrane regulator (CFTR) and CFTRpotentiators, preferably VX-770 and VX-809, or double or triplecombinations thereof.

4. USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms.

In general in single groups like HO, H₂N, OS, O₂S, NC (cyano), HOOC, F₃Cor the like, the skilled artisan can see the radical attachment point(s)to the molecule from the free valences of the group itself. For combinedgroups comprising two or more subgroups, the last or first namedsubgroup hyphenated at the end is the radical attachment point, forexample, the substituent “aryl-C₁₋₃-alkyl-” means an aryl group which isbound to a C₁₋₃-alkyl-group, the latter of which is bound to the core orto the group to which the substituent is attached.

When a compound of the present invention is depicted in the form of achemical name and as a formula, in case of any discrepancy the formulashall prevail. An asterisk may be used in sub-formulas to indicate thebond which is connected to the core molecule as defined.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

Many of the following terms may be used repeatedly in the definition ofa formula or group and in each case have one of the meanings givenabove, independently of one another.

Unless specifically indicated, according to the invention a givenchemical formula or name shall encompass tautomers and all stereo,optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Zisomers etc.) and racemates thereof as well as mixtures in differentproportions of the separate enantiomers, mixtures of diastereomers, ormixtures of any of the foregoing forms where such isomers andenantiomers exist, as well as salts, including pharmaceuticallyacceptable salts thereof and solvates thereof such as for instancehydrates including solvates of the free compounds or solvates of a saltof the compound.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds. For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

The expression “treatment” or “therapy” means therapeutic treatment ofpatients having already developed one or more of said conditions inmanifest, acute or chronic form, including symptomatic treatment inorder to relieve symptoms of the specific indication or causal treatmentin order to reverse or partially reverse the condition or to delay theprogression of the indication as far as this may be possible, dependingon the condition and the severity thereof. Thus the expression“treatment of a disease” as used herein means the management and care ofa patient having developed the disease, condition or disorder. Thepurpose of treatment is to combat the disease, condition or disorder.Treatment includes the administration of the active compounds toeliminate or control the disease, condition or disorder as well as toalleviate the symptoms or complications associated with the disease,condition or disorder.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, aceticacid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts,) also comprise a part of the invention.

As used herein the term “prodrug” refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound, for example, byhydrolysis in blood or by activation via oxidation as in case ofthioether groups. Most common prodrugs include esters and amide analogsof the parent compounds. The prodrug is formulated with the objectivesof improved chemical stability, improved patient acceptance andcompliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Ingeneral, prodrugs themselves have weak or no biological activity and arestable under ordinary conditions. Prodrugs can be readily prepared fromthe parent compounds using methods known in the art, such as thosedescribed in A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991,particularly Chapter 5: “Design and Applications of Prodrugs”; Design ofProdrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical andOcular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods inEnzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985,particularly pp. 309-396; Burger's Medicinal Chemistry and DrugDiscovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

The term “heterocyclyl” or “heterocyclic ring” means a saturated orunsaturated mono- or polycyclic-ring system containing one or moreheteroatoms selected from N, O or S(O)_(r), wherein r=0, 1 or 2,consisting of 3 to 14 ring atoms. The term “heterocycle” is intended toinclude all the possible isomeric forms.

Thus, the term “heterocyclyl” or “heterocyclic ring” includes thefollowing exemplary structures which are not depicted as radicals aseach form may be attached through a covalent bond to any atom so long asappropriate valences are maintained:

The term “heteroaryl” means a mono- or polycyclic-ring system containingone or more heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1or 2, consisting of 5 to 14 ring atoms wherein at least one of theheteroatoms is part of aromatic ring. The term “heteroaryl” is intendedto include all the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

The term “monocyclic C₅₋₇-heterocyclyl” means a saturated or unsaturatednon-aromatic monocyclic-ring system containing one or more heteroatomsselected from N, O or S(O)_(r), wherein r=0, 1 or 2, consisting of 5 to7 ring atoms. The term “monocyclic C₅₋₇-heterocyclyl” is intended toinclude all the possible isomeric forms.

Thus, the term “monocyclic C₅₋₇-heterocyclyl” includes the followingexemplary structures which are not depicted as radicals as each form maybe attached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “monocyclic C₅₋₆-heteroaryl” means a monocyclic-ring systemcontaining one or more heteroatoms selected from N, O or S(O)_(r),wherein r=0, 1 or 2, consisting of 5 or 6 ring atoms wherein at leastone of the heteroatoms is part of aromatic ring. The term “monocyclicC₅₋₆-heteroaryl” is intended to include all the possible isomeric forms.

Thus, the term “monocyclic C₅₋₆-heteroaryl” includes the followingexemplary structures which are not depicted as radicals as each form maybe attached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “bicyclic C₈₋₁₀-heterocyclyl” means a saturated or unsaturatedbicyclic-ring system including aromatic ring systems containing one ormore heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1 or 2,consisting of 8 to 10 ring atoms wherein the heteroatoms is optionallypart of the aromatic ring. The term “bicyclic C₈₋₁₀-heterocyclyl” isintended to include all the possible isomeric forms.

Thus, the term “bicyclic C₈₋₁₀-heterocyclyl” includes the followingexemplary structures which are not depicted as radicals as each form maybe attached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “annelated species of aryl or heterocyclyl” as used herein,either alone or in combination with another substituent wherein theannelated species presents as an aryl-het (a), a het-aryl (b) or ahet-het (c) annelation means a monovalent substituent derived by removalof one hydrogen from

an aromatic monocyclic system or aromatic multicyclic systems containingcarbon atoms, which is annelated to a five-, six- or seven-memberedsaturated or unsaturated (including aromatic) heterocycle containingcarbon atoms and one, two, three or four ring heteroatoms selected fromnitrogen, oxygen and sulfur or

a five-, six-, or seven-membered saturated or unsaturated (includingaromatic) heterocycle containing carbon atoms and one, two, three orfour ring heteroatoms selected from nitrogen, oxygen and sulfur, whichis annelated to an aromatic monocyclic system or aromatic multicyclicsystems containing carbon atoms or

a five-, six-, or seven-membered saturated or unsaturated (includingaromatic) heterocycle containing carbon atoms and one, two, three orfour ring heteroatoms selected from nitrogen, oxygen and sulfur, whichis annelated to a five-, six-, or seven-membered saturated orunsaturated (including aromatic) heterocycle containing carbon atoms andone, two, three or four ring heteroatoms selected from nitrogen, oxygenand sulfur.

Suitable examples of an annelated species of aryl or het include:quinolinyl, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl,benzimidazyl or purinyl.

The term “halogen” as used herein means a halogen substituent selectedfrom fluoro, chloro, bromo or iodo.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer from 4 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

In all cases of contradictions between structure and their namingstructure shall prevail.

5. PREFERRED EMBODIMENTS

-   -   The symbol A denotes a bond or is selected from the group        consisting of O, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂—O—,        —CH₂—NR^(A1)— and —NR^(A1)—, preferably bond, —CH₂— and        —CH₂CH₂—,        -   wherein        -   R^(A1) denotes hydrogen or C₁₋₆-alkyl, preferably hydrogen            or C₁₋₂-alkyl.    -   The symbol B denotes —CH₂— or —CH₂CH₂—, preferably —CH₂—, or        -   provided that A is not O or —NR^(A1), a bond.    -   The symbol D denotes a bond or —CH₂—, preferably —CH₂—.    -   The symbol E denotes a bond or —CH₂—, preferably —CH₂—.    -   The symbol F denotes optionally substituted aryl, preferably        phenyl, preferably substituted by R², R³, R⁴, R⁶, R⁷, R^(2a),        R^(3a), R^(4a), R^(6a) or R^(7a)        -   or optionally substituted heteroaryl, preferably thiophenyl,            pyridyl, pyrimidinyl or pyridonyl,        -   most preferably phenyl, 4-halo-phenyl or pyridyl,            particularly preferred phenyl.    -   The symbol G denotes a group of formula (g.1), (g.2) or (g.3)

-   -   The substituent R¹ is selected from the group consisting of        -   hydrogen, C₁₋₆alkyl, optionally substituted piperidinyl-CO—,            optionally substituted piperazinyl-CO—, optionally            substituted piperidinyl-NH—CO—, R^(1.1)—SO₂—,            R^(1.2)—C₂₋₄-alkyl-NH—CO—, H₃C—NH—CO—,            R^(1.2.4)—O—CO—CH₂—NH—CO—,            R^(1.2)—C₂₋₄-alkyl-N(C₁₋₄-alkyl)-CO—, H₃C—N(C₁₋₄-alkyl)-CO—,            R^(1.2.4)—O—CO—CH₂—N(C₁₋₄-alkyl)-CO—, R^(1.3)C₁₋₆-alkyl-CO—,            R^(1.4)—C₂₋₆-alkyl-, optionally substituted phenyl-CH₂—,            R^(1.4.3)—O—CO—CH₂—, HO—CO—CH₂— and HO—SO₂—CH₂—,        -   R^(1.5)—C₁₋₆-alkyl-CO— and R^(1.6)—C(NH)—, wherein        -   R^(1.1) is selected from the group consisting of            C₁₋₄-alkyl-, H₂NC(NH)NH—C₁₋₆-alkyl-,            R^(1.2.1)R^(1.2.2)N—C₁₋₄-alkyl-,            R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—C₁₋₄-alkyl, HOCO—C₁₋₄-alkyl-            and C₁₋₃-alkyl-OCO—C₁₋₄-alkyl-,        -   R^(1.2) is selected from the group consisting of hydrogen,            H₂NC(NH)NH—, R^(1.2.1)R^(1.2.2)N—,            R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—,            R^(1.2.3)—HN—C(NR^(1.2.3))—NH—, R^(1.2.4)—O—CO—,            R^(1.2.5)—O—CO—NH— and HO—CO—, HOSO₂—, preferably            R^(1.2.1)R^(1.2.2)N—, R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—,            R^(1.2.3)—HN—C(NR^(1.2.3))—NH—,            -   wherein            -   R^(1.2.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, more preferably C₁₋₄-alkyl, most                preferably methyl            -   R^(1.2.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, More preferably C₁₋₄-alkyl, most                preferably methyl            -   or            -   R^(1.2.1) and R^(1.2.2) together build a 4- to                7-membered hetercyclic ring containing one N-atom,                preferably a 5- or 6-membered heterocyclic ring            -   R^(1.2.3) denotes C₁₋₆-alkyl, preferably C₁₋₄-alkyl,                most preferably methyl            -   R^(1.2.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.2.5) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,        -   R^(1.3) is selected from the group consisting of hydrogen,            C₁₋₆-alkyl, C₁₋₆-alkyl-O—, optionally substituted phenyl,            R^(1.3.1)R^(1.3.2)N—, R^(1.2.1)R^(1.2.2)R^(1.2.3)N⁺—,            R^(1.2.3)—HN—C(NR^(1.2.3))—NH, H₂NC(NH)NH—, R^(1.2.4)—O—CO,            HO—CO— and HOSO₂—, wherein            -   R^(1.3.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.3.2) denotes hydrogen or C₁₋₆-alkyl,            -   or            -   R^(1.3.1) and R^(1.3.2) together build a 4- to                7-membered hetercyclic ring containing one N-atom,                preferably a 5- or 6-membered heterocyclic ring                containing one N-atom, preferably hydrogen or                C₁₋₄-alkyl,        -   R^(1.4) is selected from the group consisting of hydrogen,            R^(1.4.1)R^(1.4.2)N—, R^(1.4.1)R^(1.4.2)R^(1.4.3)N⁺—,            H₂N—C(NH)—NH—, R^(1.4.3)—HN—C(NR^(1.4.4))—NH—, optionally            substituted phenyl, R^(1.4.3)—O—CO—, R^(1.4.4)—O—CO—NH—,            HO—CO— and HOSO₂—,            -   wherein            -   R^(1.4.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.3) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R1.4.4 denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,        -   R^(1.5) is selected from the group consisting of hydrogen,            C₁₋₆-alkyl-O—, R^(1.5.1)R^(1.5.2)N—,            R^(1.5.1)R^(1.5.2)R^(1.5.3)N⁺—, H₂N—C(NH)—NH—, optionally            substituted phenyl, R^(1.5.3)—O—CO—, R^(1.5.4)—O—CO—NH—,            HO—CO—, HOSO₂—,            -   wherein            -   R^(1.5.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.5.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.5.3) denotes hydrogen or C₁₋₆-alkyl preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.5.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,        -   R^(1.6) denotes R^(1.6.1)R^(1.6.2)N—,            -   wherein            -   R^(1.6.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or methyl,            -   R^(1.6.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or methyl.        -   Preferably R¹ is selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₄-alkyl-SO₂—, C₁₋₄-alkyl-NH—CO—,            H₂N—CO—, H₂N—C₁₋₄-alkyl-, H₂N—C₁₋₄-alkyl-CO—,            H₂N—C₁₋₄-alkyl-NH—CO—, Phenyl-CO—, Phenyl-CH₂—CO—,            Phenyl-CH₂—, C₁₋₆-alkyl-CO—, C₁₋₆-alkyl-O—C₁₋₄-alkyl-CO—,            (CH₃)₂N—C₁₋₄-alkyl-, (CH₃)₂N—C₁₋₄-alkyl-NH—CO—,            (CH₃)₃N⁺—C₁₋₄-alkyl-NH—CO—, (CH₃)N⁺—C₁₋₄-alkyl-            N(C₁₋₄-alkyl)-CO—, (CH₃)₃N⁺—C₂₋₄-alkyl-,            (CH₃)₃N⁺—C₁₋₄-alkyl-CO—, H₂N—C(NH)—NH—C₁₋₆-NH—CO—,            C₁₋₆-alkyl-O—CO—, C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-,            C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-CO—,            C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-NH—CO—,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-CO—,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-NH—CO—, HOCO—C₁₋₄-alkyl-,            HOCO—C₁₋₄-alkyl-CO—, HOCO—C₁₋₄-alkyl-NH—CO—, H₂N—CNH— and            H₂NC(NH)NH—C₁₋₆-alkyl-CO—.        -   or        -   Also preferred R¹ is selected from among a group of below            listed formulas (c1) to (c5):

-   -   -   Particularly preferred R¹ denotes hydrogen or is selected            from the group consisting of C₁₋₆-alkyl, C₁₋₄-alkyl-SO₂—,            C₁₋₄-alkyl-NH—CO—, H₂N—CO—, H₂N—C₁₋₄-alkyl-,            H₂N—C₁₋₄-alkyl-CO—, H₂N—C₁₋₄-alkyl-NH—CO—, Phenyl-CO—,            Phenyl-CH₂—CO—, Phenyl-CH₂—, C₁₋₆-alkyl-CO—,            C₁₋₆-alkyl-O—C₁₋₄-alkyl-CO—, (CH₃)₂N—C₁₋₄-alkyl-,            (CH₃)₂N—C₁₋₄-alkyl-NH—CO—, (CH₃)₃N⁺—C₁₋₄-alkyl-NH—CO—,            (CH₃)₃N⁺—C₂₋₄-alkyl-, (CH₃)₃N⁺—C₁₋₄-alkyl-CO—,            H₂N—C(NH)—NH—C₁₋₆—NH—CO—, C₁₋₆-alkyl-O—CO—,            C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-, C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-CO—,            C₁₋₆-alkyl-O—CO—C₁₋₄-alkyl-NH—CO—,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-CO—,            C₁₋₆-alkyl-O—CO—NH—C₁₋₄-alkyl-NH—CO—, HOCO—C₁₋₄-alkyl-,            HOCO—C₁₋₄-alkyl-CO—, HOCO—C₁₋₄-alkyl-NH—CO— and H₂N—CNH—.

    -   The substituent R^(1s) denotes C₁₋₆-alkyl, preferably methyl.

X⁻ denotes any anion forming a pharmaceutically acceptable salt,preferably selected from among CF₃—COO⁻, Cl⁻, I⁻, Br⁻, HCOO⁻ andCH₃—COO⁻, most preferably Cl⁻ and CF₃—COO⁻.

-   -   The substituent R^(1b) is selected from the group consisting of        C₁₋₄-alkyl,        -   R^(1.4)—C₂₋₆-alkyl-, optionally substituted phenyl-CH₂—,            R^(1.4.3)—O—CO—CH₂— and HO—CO—CH₂-, preferably C₁₋₄-alkyl,            particularly preferred methyl,        -   wherein        -   R^(1.4) is selected from the group consisting of hydrogen,            R^(1.4.1)R^(1.4.2)N—, R^(1.4.1)R^(1.4.2)R^(1.4.3)N⁺—,            H₂N—C(NH)—NH—, R^(1.4.3)—HN—C(NR^(1.4.4))—NH, optionally            substituted phenyl, R^(1.4.3)—O—CO—, R^(1.4.4)—O—CO—NH—,            HO—CO— and HOSO₂—,            -   wherein            -   R^(1.4.1) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.2) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl,            -   R^(1.4.3) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl,            -   R^(1.4.4) denotes hydrogen or C₁₋₆-alkyl, preferably                hydrogen or C₁₋₄-alkyl, most preferably C₁₋₄-alkyl.    -   The symbol L denotes a bridging group —CO—NH—C₂₋₆-alkyl-NH—CO—,        —COC₁₋₆-alkyl-CO— or —C₂₋₆-alkyl-,        -   forming a compound of formula (IC),        -   whereby the molecular entities of formula (IC) connected by            L may be identical or different,

-   -   -   preferably forming a compound of formula (IC.1),        -   whereby the molecular entities of formula (IC.1) connected            by L may be identical or different,

-   -   The substituents R² and R^(2a) independently from each other are        selected from the group consisting of hydrogen, halogen, CN,        C₁₋₆alkyl, C₁₋₃-alkyl-O—, C₁₋₃-alkyl-OCO—, —COOR^(4.1),        —CONR^(4.2)R^(4.3) and —OR^(4.1), preferably hydrogen,        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl.    -   The substituents R³ and R^(3a) independently from each other are        selected from the group consisting of hydrogen, halogen, CN,        C₁₋₄alkyl, C₁₋₃-alkyl-O, —C₁₋₃-alkyl-OCO—, —COOR^(4.1),        —CONR^(4.2)R^(4.3) and —OR^(4.1), preferably hydrogen,        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl.    -   The substituents R⁴ and R^(4a) independently from each other are        selected from the group consisting of hydrogen, halogen, CN,        C₁₋₃-alkyl-O—C₁₋₃-alkyl-OCO—, —COOR^(4.1), —CONR^(4.2)R^(4.3)        and —OR^(4.1), preferably hydrogen,        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,    -   or    -   R³ and R⁴ or R^(3a) and R^(4a) together denote —O—C₁₋₃-alkyl-O—;        preferably —O—C₁₋₂-alkyl-O—.    -   The substituent R⁵ denotes Cl or Br, preferably Cl.    -   The substituent R⁶ and R^(6a) independently from each other are        selected from the group consisting of hydrogen, halogen, CN,        C₁₋₄alkyl, C₁₋₃-alkyl-O—, C₁₋₃-alkyl-OCO—, —COOR^(4.1),        —CONR^(4.2)R^(4.3) and —OR^(4.1), preferably hydrogen,        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl.    -   The substituent R⁷ and R^(7a) independently from each other are        selected from the group consisting of hydrogen, halogen, CN,        C₁₋₄alkyl, C₁₋₃-alkyl-O—, C₁₋₃-alkyl-OCO—, —COOR^(4.1),        —CONR^(4.2)R^(4.3) and —OR^(4.1), preferably hydrogen,        -   wherein        -   R^(4.1) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.2) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl,        -   R^(4.3) denotes hydrogen or C₁₋₄-alkyl, preferably hydrogen            or C₁₋₂-alkyl, particularly preferred hydrogen or methyl.    -   Any of the definitions of R¹ to R⁷ described above may be        combined with each other to form an embodiment of the invention.

6. PREPARATION

The following methods are suitable for preparing compounds of generalformula (IA), (IB) or (IC).

The compounds according to the invention may be obtained using methodsof synthesis which are known to one skilled in the art and described inthe literature of organic synthesis. General methods for functionalgroups protection and deprotection steps are described e.g. in: Greene,T. W. and Wuts, P. G. M. (eds.): Protective Groups in Organic Synthesis,third edition 1999; John Wiley and Sons, inc. Preferably the compoundsare obtained analogously to the methods of preparation explained morefully hereinafter, in particular as described in the experimentalsection.

Compounds of general formula (I) can be prepared by reactingS-methylisothioureas of formula (II) with primary amines of formula(III) in a solvent like THF, acetonitrile or DMF or in a solventmixture, preferably in the presence of a base, especially when theprimary amine (III) is applied as an acid addition salt, preferably atbetween 18° C. to 90° C.

Compounds of general formula (I) can be converted into compounds ofgeneral formula (Ia) by reaction with BOC₂O in the presence of a base,preferably triethylamine, in a solvent like e.g. THF.

Compounds of general formulas (I) and (Ia) can be modified using methodsof synthesis which are known to the one skilled in the art and describedin the literature of organic synthesis, preferably by functional groupprotection or deprotection steps, or hydrogenations. Furthermore, thegroup R¹ in compounds of general formula (Ia) can be modified underconditions not compatible with the acylguanidine group present incompounds of general formula I, preferably by alkylation of tertiaryamino groups to yield quaternary ammonium compounds.

Compounds of general formula (Ia) can be converted into compounds ofgeneral formula (I) by removal of the BOC moiety under standard acidicdeprotection conditions.

A preferred realization of Scheme 1 is Scheme 1.1.

Compounds of general formula (II) can be prepared by reactingS-methylisothiourea (which may be generated in situ from its salt byaddition of base) with a 1-(tert-butylcarbamoyl)prop1-en-2-ylcarboxylate of general formula (IV) in a solvent like DCM, THF or amixture of these solvents, preferably at between −10° C. to 25° C.

Compounds of general formula (IV) can be prepared from the respectivecarboxylic acid of general formula (V) and a2-tert-butyl-5-methyl-isoxazolium salt of general formula (VI), whichcan be applied as an isolated salt (e.g. the hexafluorophosphate salt;X═PF₆) or generated in situ from tert-butanol, 5-methylisoxazole andtrifluoromethanesulfonic acid. The latter reaction is preferablyperformed in a solvent like DMF or in a solvent mixture with theaddition of triethylamine or another base, preferably while cooling to0-10° C.

Compounds of general formula (III) can be obtained from compounds ofgeneral formula (XV) by reduction of the nitrile group, preferably byhydrogenation with raney-nickel as catalyst under hydrogen pressure inthe presence of excess ammonia in a solvent like e.g. methanol. Thegroup R^(c) in compounds of general formula (XV) can be modified usingmethods of synthesis which are known to the one skilled in the art anddescribed in the literature of organic synthesis, preferably byfunctional group protection or deprotection steps, esterifications,amidations, or hydrogenations. Depending on the nature of R^(c), thismoiety can be removed using methods of synthesis which are known to theone skilled in the art and described in the literature of organicsynthesis, especially of protective group removal to yield compounds ofgeneral formula (XVI). Compounds of general formula (XVI) can beconverted into compounds of general formula (XV) using methods ofsynthesis which are known to the one skilled in the art and described inthe literature of organic synthesis, especially by acylation,alkylation, or reductive amination.

Compounds of general formula (XV), wherein D represents —CH₂— or—CH₂—CH₂— can be prepared by reaction of alkylating agents of generalformula (VI) with 4-cyanopiperidines of general formula (VII) in asolvent like THF, wherein the compound of general formula (VII) isdeprotonated by a base, preferably LDA, n-BuLi or NaH, preferably at atemperature between −80° C. and 0° C. and wherein LG represents aleaving group, preferably Cl, Br, I, mesylate or tosylate and wherein Grepresents an acyl moiety, preferably the BOC group.

Compounds of general formula (XV), wherein A represents a bond can beprepared by double alkylation of phenylacetonitriles of general formula(IX) with bis-chloroethylamines of general formula (VIII) with theaddition of a base, preferably NaH in a solvent, preferably DMF, whereinR^(c) represents an acyl moiety, preferably the BOC group.

Compounds of general formula (X), wherein L represents chain with atleast 2 carbon atoms, can be prepared by reaction of (XI) with an acidpreferably TFA or HCl in a solvent like THF, dioxane, dichloromethane,DMF or water, preferably at a temperature between 10° C. and 50° C.

Compounds of general formula (XII), wherein L represents chain with atleast 2 carbon atoms can be prepared by a reaction sequence startingwith (XIII) protecting it with BOC anhydride, quaternization withalkylhalogenide preferably alkyliodide in a solvent like acetone, THF,dioxane or dichloromethane, preferably at a temperature between 10° C.and 50° C. followed by deprotection with acids.

Compounds of general formula (XIV), wherein L represents chain with atleast 2 carbon atoms can be prepared by reaction compounds of generalformule (X) with 1H-1.2.4-triazole-1-carboxamidine orS-methylisothioureas in DMF preferably at a temperature between 50° C.and 90° C.

7. EXAMPLES 7.1 SYNTHESIS OF INTERMEDIATES

Intermediate A.61

3,5-Diamino-6-chloropyrazine-2-carboxylic acid

A mixture of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate (100 g;494 mmol), methanol (1 l) and NaOH (6 mol/l in water; 240 mL; 1.44 mol)is refluxed for 3 h. The mixture is allowed to cool to r.t. and thenneutralized by addition of hydrochloric acid (6 mol/l in water; approx.240 mL). Water (200 mL) is added. The precipitate formed is filtered offwith suction, washed with water and dried at 60° C.

Yield: 99.6 g (107% of theory)

C₅H₅ClN₄O₂ ESI Mass spectrum: m/z=189 [M+H]+; m/z=187 [M−H]⁻

Intermediate A.62

3,5-Diamino-6-bromopyrazine-2-carboxylic acid is prepared from methyl3,5-diamino-6-bromopyrazine-2-carboxylate (which is prepared from methyl3,5-diamino-6-chloropyrazine-2-carboxylate as described in J. Med. Chem.1967, 10, 66-75) analogously to the procedure described for thesynthesis of intermediate A.61

Intermediate B.61

1-(tert-Butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate

Stage 1:

A mixture of tert-butanol (21.0 mL; 226 mmol) and 5-methylisoxazole(18.0 mL; 221 mmol) is cooled with an ice-bath. Trifluoromethanesulfonicacid (20.0 mL; 221 mmol) is added dropwise with continued cooling. Theresulting mixture is stirred for 1 h without further cooling.

Stage 2:

To a solution or suspension of 3,5-diamino-6-chloropyrazine-2-carboxylicacid (Intermediate A.61; 14.0 g; 74.2 mmol) and triethylamine (31.0 mL;222 mmol) in DMF (100 mL) is added the mixture prepared in stage 1. Theresulting mixture is stirred for 4 h at r.t. Ice-water is added withstirring. The precipitate formed is filtered off with suction, washedwith water and dried at 65° C. to yield the title compound.

Yield: 18.2 g (75% of theory)

C₁₃H₁₈ClN₅O₃ ESI Mass spectrum: m/z=328 [M+H]+; m/z=326 [M−H]⁻

TLC (Silica; DCM/MeOH 9:1): R_(f)=0.4

Intermediate B.62

1-(2-Methyl-2-butyl-carbamoyl)prop-1-en-2-yl3,5-diamino-6-bromopyrazine-2-carboxylate

Stage 1:

A mixture of 2-methyl-2-butanol (5.75 mL; 51 mmol) and 5-methylisoxazole(4.42 mL; 51 mmol) is cooled with an ice-bath. Trifluoromethanesulfonicacid (4.84 mL; 54 mmol) is added dropwise with continued cooling. Theresulting mixture is stirred over night without further cooling.

Stage 2:

To a solution or suspension of 3,5-diamino-6-bromopyrazine-2-carboxylicacid (Intermediate A.62; 5.00 g; 21.5 mmol) and triethylamine (7.48 mL;54 mmol) in DMF (50 mL) cooled with an ice-bath is added dropwise themixture prepared in stage 1. The resulting mixture is stirred for 4 h atr.t., then poured on ice-water. The precipitate formed is filtered offwith suction, washed with water and dried at 50° C. to yield the titlecompound.

Yield: 7.53 g (91% of theory)

C₁₄H₂₀BrN₅O₃ ESI Mass spectrum: m/z=386 [M+H]+; m/z=384 [M−H]⁻

Intermediate C.61

3,5-Diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide

To NaOH (1 mol/l in water; 9.2 mL; 9.2 mmol) is addedS-methylisothiourea sulfate (1.78 g; 6.1 mmol. The mixture is stirreduntil complete solution is achieved. TBME/THF (1:1; 30 mL) and then1-(tert-butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate (Intermediate B.61; 2.00 g;6.10 mmol) are added and the mixture is stirred at r.t. over night, thenwater (6 mL) is added. The precipitate formed is filtered off withsuction, washed successively with water, methanol and then with diethylether and then dried at 50° C. to yield the title compound.

Yield: 1.33 g (84% of theory)

C₇H₉ClN₆OS ESI Mass spectrum: m/z=261 [M+H]+; m/z=259 [M−H]⁻

Intermediate C.62

3,5-Diamino-6-bromo-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide

To NaOH (1 mol/l in water; 30 mL; 30 mmol) is added S-methylisothioureasulfate (5.42 g; 19.5 mmol. The mixture is stirred until completesolution is achieved. TBME/THF (1:1; 100 mL) and then1-(2-methyl-2-butyl-carbamoyl)prop-1-en-2-yl3,5-diamino-6-bromopyrazine-2-carboxylate (Intermediate B.62; 7.52 g;19.5 mmol) are added and the mixture is stirred at r.t. over night, thenwater (100 mL) is added. The precipitate formed is filtered off withsuction, washed with THF/water (1:2) and then dried at 50° C. to yieldthe title compound.

Yield: 5.44 g (92% of theory)

C₇H₉BrN₆OS ESI Mass spectrum: m/z=305 [M+H]+

D.2

To a solution of 21.10 g di-isopropylamine in 300 mL anhydrous THF isadded 83.7 mL 2.5 M solution of n-butyl lithium in THF dropwise at −78°C. The resultant solution is stirred at this temperature for 30 min.Then a solution of 40.00 g 1-N-BOC-4-cyanopiperidine in 300 mL THF isadded dropwise. After 1 h stirring 51.99 ml (2-bromo-ethyl)-benzene isadded dropwise. After the addition the reaction mixture is allowed towarm up to room temperature and stirred overnight. 100 mL water is addedto quench the reaction. THF is removed to leave a slurry which ispartitioned between ethyl acetate and water. After a separation theorganic layer is washed with sat. aq. NH₄Cl and brine, dried with Na₂SO₄and concentrated under reduced pressure. Purification by columnchromatography results in 57.23 g of intermediate D.2. TLC (EA/PE 1/8)R_(f): 0.4.

D.8

Intermediate D.8 is obtained using a similar procedure as described forintermediate D.2 utilizing benzyl bromide as alkylating agent. TLC(ethylacetate (EA)/petroleum ether (PE)) 1/9) R_(f): 0.3.

C.17

Intermediate C.17 is obtained using a similar procedure as described forintermediate D.2 using 4-(2-bromoethyl)benzoic acid as alkylating agent.TLC (MeOH/dichloromethane (DCM) 5/95) R_(f): 0.4.

C.18

Intermediate C.18 is obtained treating C.17 with ammonia and TBTU indichloromethane.

B.17

To a solution of 4.00 g intermediate C.17 in 40 ml dry DMF are added5.40 g K₂CO₃ and then 2.40 ml methyl iodide dropwise. The reactionmixture is stirred at room temperature for 12 h. Then water is added andthe mixture is extracted with diethyl ether. The organic phases arepooled, dried over Na₂SO₄ and evaporated. The resulting crude product ispurified by FC resulting in 3.40 g of intermediate B.17. TLC (EA/PE 2/3)R_(f): 0.6.

D.45

To a solution of 2.00 g N-BOC-N,N-bis(2-chloroethyl)amine and 1.10 g(2-methoxyphenyl)-acetonitrile in 15 ml THF and 5 ml DMF is added 0.78 gof NaH in portions at r.t. and the mixture is stirred at 55° C. for 16h. The reaction is quenched by addition of cold water and extracted withethyl acetate. The organic layer is washed with brine and water, driedover Na₂SO₄ filtered and evaporated under reduced pressure. The crudesolid is triturated with a mixture of CHCl₃ and ether filtered and driedresulting in 1.0 g of intermediate D.45. TLC (EA:PE 3/7) R_(f): 0.6.

D.43 and D.44

D.43 and D.44 are obtained using a similar procedure as described forintermediate D.45 utilizing the corresponding benzyl cyanides.

C.2

A mixture of 2.50 g of piperidine D.2 and 40 ml 25% TFA indichloromethane are stirred for 1.5 h at room temperature. The solventis evaporated, methanolic hydrochloric acid is added and the solventevaporated again giving rise to 2.53 g of intermediate C.2.

ESI-MS m/z: 215. The corresponding TFA salt of C.2 is obtained bypurification of the crude product by preparative reversed-phase HPLCwith TFA as modifier.

C.8, C.43, C.44 and C.45

The following intermediates are obtained using a similar procedure asdescribed for intermediate C.2 with a modified workup: neutralization ofthe reaction mixture with saturated NaHCO₃ solution followed by anaqueous workup.

B.2

A mixture of 2.30 g piperidine hydrochloride C.2, 1.08 ml2-isocyanato-propane, 1.99 ml triethylamine and 50 ml THF are stirred at50° C. for 2 h. The reaction mixture is concentrated under reducedpressure and water is added and finally extracted with dichloromethane.The combined organic phases are dried over MgSO₄ and evaporated yielding1.65 g of intermediate B.2.

ESI-MS m/z: 300, 344

B.4, B.8, B.12, B.18, B.19, B.43, B.44, B.45, B.48 and B.49

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.2 utilizing the corresponding isocyanates.DCM can be used as an alternative solvent.

B.10

0.22 ml Triethylamine is added slowly to a mixture of 0.34 g piperidinetrifluoroacetate C.2, 0.32 g triphosgene and 5 ml dichloromethane. Themixture is stirred at room temperature for 4 h and 0.17 mlN,N-dimethyl-ethylendiamine are added and the reaction mixture isstirred at room temperature overnight. The reaction mixture isconcentrated under reduced pressure, a mixture of DMF, methanol and TFAis added, and the resulting mixture is filtered and purified bypreparative reversed-phase HPLC. The product-containing fractions arepooled and evaporated. The resulting residue is taken up withdichloromethane and a 4N NaOH solution is added. The organic phase isseparated by a phase separator cartridge. Evaporation gives rise to 0.22g of intermediate B.10. ESI-MS m/z: 329.

B.33 B.34 B.39 B.35 B.36 B.38 B.40, B.51, B.52, B.53, B.54, B.55 andB.56

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.10 using the corresponding amines.

B.53

To a suspension of 0.75 g of 1,1′-carbonyldi(1,2,4-triazole) in 5 ml ofTHF, a solution of 0.5 ml of 1-methylpiperazine dissolved in 5 ml of THFis added dropwise. The reaction mixture is stirred at room temperaturefor 40 minutes, then a solution of 0.5 g of intermediate C.2 (as freebase) in 5 ml of THF is added dropwise and the reaction mixture isstirred at 60° C. overnight. The solvent is evaporated, the crudeproduct obtained is partitioned between dichloromethane and water andthe organic phase is separated, dried over sodium sulfate andconcentrated under vacuum. The crude product is purified by flashchromatography (eluent: AcOEt/MeOH=80/20) and re-purified by preparativeLC-MS (reverse phase; NH4COOH) 150 mg of intermediate B.53 are obtained.

B.54 and B.55

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.53 using the corresponding amines

B.56

B.56 is prepared following a similar procedure as in the preparation ofB.53 starting from commercially available 4-cyano-4-phenylpiperidine andN,N-dimethylethylenediamine.

B.3

Intermediate B.3 is prepared by reductive amination of intermediate C.2with formaldehyde and NaCNBH₃ in THF.

B.7 and B.21

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.3 utilizing the corresponding carbonylcompounds.

B.5

Intermediate B.5 is prepared by acylation of intermediate C.2 withbenzoyl chloride and triethylamine in dichloromethane.

B.1, B.11, B.13, B.14, B.9 B.20 and B.47

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.5 using the corresponding acid chlorides.

B.22

To a mixture of 1.07 g intermediate C.2, 1.42 g N-BOC-beta alanine, 2.5g EDCI in 50 ml anhydrous THF is added 4.90 ml triethylamine and 0.1 gDMAP. The reaction mixture is stirred at r.t. overnight. Water is addedand the mixture concentrated and extracted with ethyl acetate. Thecombined organic phases are washed with sat. aq. NH₄Cl and brine, driedover Na₂SO₄ and concentrated. The residual crude product is purified byFC giving rise to intermediate B.22

B.23, B.25, B.24, B.26, B.27 and B.42

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.22 using the corresponding acids.

B.6

Intermediate B.6 is prepared by alkylation of intermediate C.2 withbenzyl bromide and Cs₂CO₃ in acetonitrile.

B.15

The intermediate B.15 was obtained using the following procedure.

0.1 g C.2 was dissolved in 5 ml acetone and 0.1 g K₂CO₃ followed by dropwise addition of methyl iodide at room temperature. The resultingreaction mixture was stirred for 16 hours. Then the reaction mixture wasdiluted with ethyl acetate, washed with water followed by brine. Theorganic layer was dried over Na₂So₄ and concentrated under reducedpressure. The crude product was purified by chromatography eluting with18% ethyl acetate/petoleum ether on a silica gel column

B.50

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.15 using methyl iodide.

B.16, B.28, B.29, B.30, B.31, B.32, B.37 B.41 and B.46

The following intermediates are obtained using a similar procedure asdescribed for intermediate B.6 using the corresponding alkyl halides asalkylating agents, K₂CO₃ and acetone.

Starting Material: 3-Carboxy-propyl-trimethyl-ammonium chloride

A.2

A suspension of 1.83 g of nitrile B.2, 0.40 g Raney-Nickel and 40 ml ofa methanolic solution of ammonia are hydrogenated at room temperatureand 3 bar H₂ for 23 h. In case of incomplete conversion additionalcatalyst and solvent are added and hydrogenation is continued for 5 h at50° C. The catalyst is removed by filtration and the filtrate evaporatedgiving rise to 1.95 g of intermediate A.2. ESI-MS m/z: 304

A.1, A.3, A.4, A.5, A.6, A.7, A.10, A.11, A.12, A.13, A.14, A.15, A.16,A.17, A.18, A.19, A.22, A.23, A.25, A.28, A.29, A.32, A.33, A.34, A.39,A.48, A.51, A.52, A.53, A.54, A.55, A.56 and A.57

The following intermediates are obtained from the corresponding nitrilesusing a similar procedure as described for intermediate A.2.

A.59

To a solution of 50 mg of intermediate B.55 in 3 ml of THF, 0.1 ml ofborane tetrahydrofuran complex is added dropwise. The reaction mixtureis stirred at room temperature for 30 min, then at 40° C. for 3 h. 0.1ml of borane tetrahydrofuran complex is added again and the reactionmixture is stirred at 50° C. overnight. The reaction mixture ispartitioned between dichloromethane and water, the organic phase iswashed with a saturated NaHCO3 water solution, dried over phaseseparator and concentrated under vacuum to give 42 mg of intermediateA.59.

A.60

To a solution of 1 g of intermediate B.56 in 20 ml of THF stirred at−78° C., 1.2 ml of a 2M solution of lithium aluminium hydride in THF isadded dropwise. The mixture is allowed to reach room temperature andstirred overnight. The solvent is concentrated, the reaction mixture ispartitioned between dichloromethane and water and organic phase is driedover phase separator and concentrated under vacuum to give 500 mg ofcrude product. 200 mg of this crude product are purified by preparativeLC-MS (reverse phase; NH₄COOH). 60 mg of pure intermediate A.60 areobtained.

7.2 SYNTHESIS OF EXAMPLES Example 14-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxylicacid tert-butyl ester

A mixture of 80 mg (0.3 mmol)4-aminomethyl-4-phenethyl-piperidine-1-carbocylic acid tert-butyl ester(A.55) and 104 mg (0.3 mmol)1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea(intermediate C.61) in 2 ml acetonitrile is stirred at 70° C. for 48hours. Then the reaction mixture is concentrated under reduced pressureand the residue is purified by preparative reverse phase HPLC (gradientof acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractionscontaining the title compound were concentrated under reduced pressure.

Yield: 116 mg.

ESI mass spectrum: [M+H]⁺=531

Retention time HPLC: 2.51 min (method M1).

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 1

Starting IC50 ESI+ Ret. HPLC Example A R¹ R² R³ R⁴ material [μM] (M +H)+ [min] Method 1.1  —CH₂—CH₂—

H H H A.1  0.034 509 1.21  M2 1.2  —CH₂—CH₂—

H H H A.2  0.008 516 1.28  M2 1.3  —CH₂—CH₂—

H H H A.3  0.033 445 1.67  M1 1.4  —CH₂—CH₂—

H H H A.4  0.027 474 1.21  M2 1.5  —CH₂—CH₂—

H H H A.5  0.034 535 2.23  M1 1.6  —CH₂—CH₂—

H H H A.6  0.040 521 1.90  M2 1.7  —CH₂—CH₂—

H H H A.7  0.063 473 0.95  M2 1.8  CH2

H H H A.8  0.017 502 1.25  M2 1.9  —CH₂—CH₂—

H H H A.9  0.011 503 1.41  M2 1.10 —CH₂—CH₂—

H H H A.10 0.036 545 1.42  M4 1.11 —CH₂—CH₂—

H H H A.11 0.017 515 1.49  M2 1.12 —CH₂—CH₂—

H H H A.12 0.012 502 1.30  M2 1.13 —CH₂—CH₂—

H H H A.13 0.013 501 1.36  M2 1.14 —CH₂—CH₂—

H H H A.14 0.020 545 1.23  M2 1.15 —CH₂—CH₂—

H H H A.15 0.091 459 (M + ) 1.05  M2 1.16 —CH₂—CH₂—

H H H A.16 0.002 503 1.07  M2 1.17 —CH₂—CH₂—

H H COOMe A.17 0.056 589 1.18 —CH₂—CH₂—

H H H A.18 0.028 546 1.30  M2 1.19 —CH₂—CH₂—

H H H A.19 0.024 560 1.33  M2 1.20 —CH₂—

H H H A.20 0.075 531 1.04  M6 1.21 —CH₂—

H H H A.21 0.089 431 1.22 —CH₂—CH₂—

H H H A.22 0.037 602 1.26  M7 1.23 —CH₂—CH₂—

H H H A.23 0.026 502 1.19  M6 1.24 —CH₂—

H H H A.24 0.027 574 1.19  M8 1.25 —CH₂—CH₂—

H H H A.25 0.018 588 1.27  M7 1.26 —CH₂—

H H H A.26 0.019 616 1.27  M7 1.27 —CH₂—

H H H A.27 0.033 588 1.24  M7 1.28 —CH₂—CH₂—

H H H A.28 0.036 588 1.08  M7 1.29 —CH₂—CH₂—

H H H A.29 0.086 516 0.90  M7 1.30 —CH₂—

H H H A.30 0.070 489 1.13  M8 1.31 —CH₂—

H H H A.31 0.287 502 0.87  M7 1.32 —CH₂—CH₂—

H H H A.32 0.046 502 0.90  M7 1.33 —CH₂—CH₂—

H H H A.33 0.007 617 1.14  M6 1.34 —CH₂—CH₂—

H H H A.34 0.010 631 1.18  M6 1.35 —CH₂—

H H H A.35 0.011 603 1.65  M5 1.36 —CH₂—

H H H A.36 0.018 617 1.68  M5 1.37 —CH₂—

H H H A.37 0.064 574 1.42  M5 1.38 —CH₂—

H H H A.38 0.042 545 1.38  M4 1.39 —CH₂—CH₂—

H H H A.39 0.023 559 1.44  M4 1.40 —CH₂—

H H H A.40 0.029 531 1.35  M5 1.41 —CH₂—

H H H A.41 0.091 488 1.20  M5 1.42 bond

H H H A.42 0.025 503 2.28  M1 1.43 bond

H H H A.43 0.041 488 1.52  M3 1.44 bond

H —O—CH2—O— A.44 0.046 532 1.56  M3 1.45 bond

O—Me H H A.45 0.066 533 1.78  M3 1.46 —CH₂—

H H H A.46 0.061 517 1.83  M3 1.47 bond

H H H A.47 0.029 517 1.000 M6 1.48 —CH₂—CH₂—

H H H A.51 0.13 516 1.0  M7 1.49 —CH₂—CH₂—

H H H A.52 0.022 530 1.01  M7 1.50 —CH₂—CH₂—

H H H A.53 0.015 558 1.50  M5 1.51 —CH₂—CH₂—

H H COOMe A.54 1.52 —CH₂—CH₂—

H H CONH2 A.56

Example 1.53

To a solution of 140 mg (0.36 mmol) of intermediate A.57 in 2.5 ml ofDMF, 0.13 ml of N,N-diisopropylethilamine is added. The reaction mixtureis stirred at room temperature for 10 minutes then 85 mg (0.33 mmol) of1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea isadded. The reaction mixture is heated at 70° C. for 3 hours.

The solvent is removed and the crude product obtained is purified byflash chromatography (first eluent: AcOEt/MeOH=90/10 in order to removeimpurities; second eluent dichloromethane/MeOH/NH3 from 90/10/0.1 to50/50/0.1 to give the desired product).

Yield: 55 mg.

IC50 [μM]=0.014

ESI mass spectrum: [M+H]⁺=557

Retention time HPLC: 5.60 min (method M9).

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 1:1

Starting IC50 ESI+ Ret. HPLC Example A R¹ R² R³ R⁴ material [μM] (M +H)+ [min] Method 1.54 —CH₂—CH₂—

H H H A.58 0.046 571 5.38 M10 1.55 —CH₂—CH₂—

H H H A.59 n.a. 629 3.52 M11 1.56 bond

H H H A.60 n.a. 517 3.08 M11

Example 2N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-(4-phenethyl-piperidin-4-ylmethyl-guanidine

A mixture of 50 mg (0.3 mmol)4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxylicacid tert-butyl ester (Example 1) in 1 ml dichloromethane is stirredwith 250 μl trifluoroacetic acid at room temperature for 2 h. Then thereaction mixture is concentrated under reduced pressure.

Yield: 40 mg.

ESI mass spectrum: [M+H]⁺=431

Retention time HPLC: 1.78 min (method M1).

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 2

Starting IC50 ESI+ Ret. Methode Example A R¹ R² R³ R⁴ material [μM] (M +H)+ [min] HPLC 2.1  —CH₂—CH₂—

H H COOMe 1.17 0.394 489 2.2  —CH₂—CH₂—

H H H 1.22 0.019 502 2.3  —CH₂—CH₂—

H H H 1.23 0.023 530 1.03 M7 2.4  —CH₂—

H H H 1.24 0.059 508 (M + CL) 0.90 M6 2.5  —CH₂—CH₂—

H H H 1.28 0.065 488 0.89 M6 2.6  —CH₂—CH₂—

H H H 1.34 0.028 531 1.57 M4 2.7  —CH₂—CH₂—

H H H 1.33 0.016 517 1.56 M4 2.8  —CH₂—

H H H 1.26 0.061 516 0.97 M7 2.9  —CH₂—

H H H 1.27 0.093 488 0.96 M7 2.10 bond H O—Me H H 1.45 0.200 433 1.26 M32.11 —CH₂— H H H H 1.46 0.055 417 1.31 M3 2.12 —CH₂—

H H H 1.35 0.017 503 0.93 M6 2.13 —CH₂—

H H H 1.36 0.025 517 0.93 M6 2.14 —CH₂—

H H H 1.37 0.12  474 0.85 M6

Example 3(4-(N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]4-phenethyl-piperidin-1-yl)acetic acid

A mixture of 145 mg (0.23 mmol){4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidin-1-yl}-aceticacid methyl ester (Example 1.16) in 5 ml methanol and 235 μl 4 N NaOH isstirred at 50° C. for 1 hour. Then the solution is acidified with 470 μl4 N HCl and concentrated under reduced pressure. The residue is purifiedby preparative reverse phase HPLC (gradient of acetonitrile andwater+0.2% trifluoroacetic acid, 25° C.). Fractions containing the titlecompound were concentrated under reduced pressure.

Yield: 35 mg.

ESI mass spectrum: [M+H]⁺=489

Retention time HPLC: 1.33 min (method M2)

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 3

Starting IC50 ESI+ Ret. Methode Example A R1 R2 R3 R4 material [μM] (M +H)+ [min] HPLC 3.1 —CH₂—CH₂—

H H H 1.14 0.040  531 1.21 M2 3.2 —CH₂—CH₂—

H H H 1.19 0.149  546 1.43 M2 3.3 —CH₂—CH₂—

H H H 1.18 0.0101 532 1.27 M2

Example 44-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxamidine

A mixture of 70 mg (0.15 mmol)N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N′-(4-phenethyl-piperidin-4-ylmethyl-guanidine(Example 2), 124 μl triethylamine and 28 mg (0.19 mmol)1H-1.2.4-triazole-1-carboxamidine monohydrochloride in 5 ml DMF isstirred at 70° C. for 2 hours. Then 1 ml methanol is added and themixture is purified by preparative reverse phase HPLC (gradient ofacetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractionscontaining the title compound were concentrated under reduced pressure.

Yield: 15 mg.

ESI mass spectrum: [M+H]⁺=473

Retention time HPLC: 0.93 min (method M7)

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 4

Starting IC50 ESI+ Ret. Methode Example A R¹ R² R³ R⁴ material [μM] (M +H)+ [min] HPLC 4.1 —CH₂—CH₂—

H H H 2.2 0.012 544 1.01 M7 4.2 —CH₂—CH₂—

H H H 2.3 0.018 570 (M − H)− 1.51 M4

Example 5(2-((4-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carbonyl)-amino)-ethyl]-trimethyl-ammoniumchloride

1.55 g4-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxylicacid (2-dimethylamino-ethyl)-amide (example 1.40), 0.9 ml triethylamineand 1.1 g BOC anhydride were dissolved in 50 ml THF and stirred overnight. The organic layer is separated and concentrated under reducedpressure.

Yield: 1.3 g

A mixture of 1.3 g Ex. 5.A and 200 μl methyl iodide in 10 ml acetone isstirred overnight at room temperature. Then the reaction mixture isconcentrated under reduced pressure and 5 ml of a 50% solution oftrifluoroacetic acid in dichloromethane is added and stirred for 2 h atroom temperature. Then the mixture is co-evaporated with methanolichydrochloric acid. The residue is purified via preparative reverse phaseHPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25°C.). Fractions containing the title compound were concentrated underreduced pressure and finally co-evaporated with methanolic hydrochloricacid.

Yield: 820 mg.

ESI mass spectrum: [M]⁺=559

Retention time HPLC: 0.97 min (method M7)

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 5

Starting IC50 ESI+ Ret. Methode Example A R¹ R² R³ R⁴ material [μM] (M +H)+ [min] HPLC 5.1 —CH₂—CH₂—

H H H 1.39 0.027 573 (M + ) 1.013 M7 5.2 —CH₂—CH₂—

H H COOMe 1.51 0.074 617 1.01  M7 5.3 —CH₂—CH₂—

H H CONH2 1.52 0.12  301 (M + +) 0.80  M7 5.4 —CH₂—CH₂—

H H H 1.53 0.051 571 2.80  M9 5.5 —CH₂—CH₂—

H H H 1.54 0.052 585 3.47  M11 5.6 —

H H H 1.56 n.a. 531 4.88  M11

Example 6

A mixture of 115 mg A.48 and 104 mg (0.3 mmol)1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea in 25ml THF are stirred at 70° C. for 80 hours. Then the reaction mixture isconcentrated under reduced pressure and the residue is purified viachromatography (Silica, dichloromethane/methanol plus 10% ammonia 9:1 to6/4). Fractions containing the title compound were concentrated underreduced pressure.

Yield: 27 mg.

ESI mass spectrum: [M+H]⁺=1001

Retention time HPLC: 1.41 min (method M2).

The following compounds are prepared accordingly from starting materialsas indicated:

TABLE 6 Starting IC50 ESI+ Ret. Methode Example Structure material [μM](M + H)+ [min] HPLC 6.1

A.49 0.097 (M + H)/ 2 + 515 1.52 M2

Example 7N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-(4-phenethyl-1-phenylacetyl-piperidin-4-ylmethyl)-guanidine

To a mixture of 70 mg (0.14 mmol)N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N′-(4-phenethyl-piperidin-4-ylmethyl)-guanidine(example 2) and 118 μl Hunig's base in 5 ml dichloromethane 27 μM (0.21mmol) phenacetylchloride is dropwise added and stirred at roomtemperature overnight. Then the mixture concentrated under reducedpressure. The residue is purified via preparative reverse phase HPLC(gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.).Fractions containing the title compound were concentrated under reducedpressure.

Yield: 9 mg.

ESI mass spectrum: [M+H]⁺=549

Retention time HPLC: 1.42 min (method M2)

Example 84-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxylicacid propylamide

To a mixture of 100 mg (0.198 mmol)N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N′-(4-phenethyl-piperidin-4-ylmethyl)-guanidine(example 2) and 29 μl DBU in 5 ml THF 12 μM (0.2 mmol) N-propylisocyanatis dropwise added and stirred at room temperature for 2 h. Then themixture is concentrated under reduced pressure. The residue is purifiedvia preparative reverse phase HPLC (gradient of acetonitrile andwater+0.2% trifluoroacetic acid, 25° C.). Fractions containing the titlecompound were concentrated under reduced pressure.

Yield: 10 mg.

ESI mass spectrum: [M+H]⁺=516

Retention time HPLC: 2.2 min (method M1)

Example 9N-[1-(2-Amino-acetyl)-4-phenethyl-piperidin-4-ylmethyl-N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine

A mixture of 130 mg (0.35 mmol)[2-(4-aminomethyl-4-phenethyl-piperidin-1-yl)-2-oxo-ethyl]-carbamic acidtert-butyl ester (A.50) and 80 mg (0.3 mmol)1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea in 5ml tetrahydrofuran is stirred at 70° C. overnight. Then the reactionmixture is concentrated under reduced pressure and the residue ispurified via preparative reverse phase HPLC (gradient of acetonitrileand water+0.2% trifluoroacetic acid, 25° C.). Fractions containing thetitle compound were concentrated under reduced pressure. Then theresidue is co-evaporated with methanolic hydrochloric acid in order toremove the protecting group.

Yield: 37 mg.

ESI mass spectrum: [M+H]⁺=488

Retention time HPLC: 1.08 min (method M7).

Example 104-{4-[N′-(3,5-Diamino-6-bromo-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidin-1-yl}-4-oxo-butyricacid methyl ester

The compound is prepared as described for example 1.14 applying3,5-diamino-6-bromo-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide(intermediate C.62) instead of intermediate C.61.

ESI mass spectrum: [M+H]⁺=589

Retention time HPLC: 0.72 min (method M12)

IC50 [μM]=0.032

Example 114-{4-[N′-(3,5-Diamino-6-bromo-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidin-1-yl}-4-oxo-butyricacid

The compound is prepared analogously to the procedure described for thesynthesis of example 3, applying example 10 as starting material.

ESI mass spectrum: [M+H]⁺=575

Retention time HPLC: 0.49 min (method M13)

IC50 [μM]=0.502

8. ANALYTICAL METHODS

HPLC/MS Methods

Method: M1

Waters ZQ2000; Waters 1515 pump, Waters PDA 996 Detector, Waters 2747Injector

Mobile Phase: A: Water+0.1% formic acid

-   -   B: Acetonitrile+0.1% formic acid

Gradient:

time in min % A % B flow rate in ml/min 0.00 95.0 5.0 1.00 0.10 95.0 5.01.00 3.10 2.00 98.00 1.00 4.50 2.00 98.00 1.00 5.00 95.0 5.0 1.00

Stationary Phase: X-terra™ MS C18 2.5 μm 4.6 mm×30 mm

Column temperature about. 25° C.

Diode array detection wave length range 210-420 nm

mass range m/z 80 to 800

Ionization: ESI positive

Method: M2

Waters ZQ2000; Waters 1515 Pump, Waters PDA 996 Detector, Waters 2747Injector

Mobile Phase: A: water+0.1% formic acid

-   -   B: Acetonitrile+0.1% formic acid

Gradient:

time in min % A % B flow rate in ml/min 0.00 95.0 5.0 1.5 2.00 0.0 1001.5 2.50 0.0 100 1.5 2.60 95.0 5.0 1.5

Stationary Phase: X-terra™ MS C18 2.5 μm 4.6 mm×30 mm

Column temperature about. 25° C.

Diode array detection range 210-420 nm

Mass range m/z 80 to 800

Ionization: ESI positive/negative

Method: M3 Analytical column: XBridge C18 (Waters technologies)

XBridge C18, 4.6×30 mm, 2.5 μm column temperature 60° C.

Mobile phase A: H2O:trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol:trifluoroacetic acid 99.9:0.1

Gradient:

time in min % A % B flow rate in ml/min 0.0 95 5 4 0.05 95 5 3 2.05 0100 3 2.10 0 100 4 2.35 0 100 4

Method: M4

Analytical column: XBridge C18 (Waters technologies)

XBridge C18, 4.6×30 mm, 2.5 μm column temperature 60° C.

Mobile phase A: H2O:trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min % A % B flow rate in ml/min 0.0 95 5 4 0.05 95 5 3 2.05 0100 3 2.10 0 100 4.5 2.40 0 100 4.5

Method: M5

Analytical column: Sunfire C18 (Waters technologies)

Sunfire C18, 4.6×30 mm, 2.5 μm column temperature 60° C.

Mobile phase A: H2O:trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min % A % B flow rate in ml/min 0.0 95 5 4 0.05 95 5 3 2.05 0100 3 2.10 0 100 4.5 2.40 0 100 4.5

Method: M6

Analytical column: XBridge C18 (Waters technologies)

XBridge C18, 3.0×30 mm, 2.5 μm column temperature 60° C.

Mobile phase A: H2O:trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min % A % B flow rate in ml/min 0.0 95 5 2.2 0.30 95 5 2.2 1.500 100 2.2 1.55 0 100 2.9 1.65 0 100 2.9

Method: M7

Analytical column: Sunfire C18 (Waters technologies)

Sunfire C18, 3.0×30 mm, 2.5 μm column temperature 60° C.

Mobile phase A: H2O:trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min % A % B flow rate in ml/min 0.0 95 5 1.8 0.25 95 5 1.8 1.700 100 1.8 1.75 0 100 2.5 1.90 0 100 2.5

Method: M8

Analytical column: XBridge C18 (Waters technologies)

XBridge C18, 3.0×30 mm, 2.5 μm column temperature 60° C.

Mobile phase A: H2O:Ammonia 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min % A % B flow rate in ml/min 0.0 95 5 2.2 0.30 95 5 2.2 1.500 100 2.2 1.55 0 100 2.9 1.70 0 100 2.9

Method: M9

Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ singlequadrupole

Column: Synergi Hydro RP100A, 2.5 μm, 3×50 mm

Mobile phase: A=H2O 90%+10% CH3CN+NH4COOH 5 mM

-   -   B=CH3CN 90%+H2O 10%

Gradient:

time in min % A % B flow rate in ml/min 0.0 100 0 1.2 4.00 0 100 1.25.30 0 100 1.2 5.50 100 0 1.2 6.00 100 0 1.2

Detection: UV 254 nm

Detection: Finnigan MSQ, single quadrupole

Ion source: APCI+/APCI−

Scan range: 100-900 amu

Method: M10

Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ singlequadrupole

Column: Synergi Hydro RP100A, 2.5 μm, 3×50 mm

Mobile phase: A=H2O 90%+10% CH3CN+NH4COOH 5 mM

-   -   B=CH3CN 90%+H2O 10%

Gradient:

time in min % A % B flow rate in ml/min 0.0 100 0 1.2 1.5 100 0 1.2 9.000 100 1.2 10.50 0 100 1.2 11.00 100 0 1.2 12.00 100 0 1.2

Detection: UV 254 nm

Detection: Finnigan MSQ, single quadrupole

Ion source: APCI+/APCI−

Scan range: 100-900 amu

Method: M11

Instrument: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro MicroTriple quadrupole

Column: Atlantis dC18 5 □m 4.6×50 mm, Temp 35° C.

Mobile phase: A=H2O 90%+10% CH₃CN+CF₃COOH 0.05%

-   -   B=CH₃CN 90%+10% H₂O

Gradient:

time in min % A % B flow rate in ml/min 0.0 100 0 1.3 0.70 100 0 1.3 4.50 100 1.3 5.8 0 100 1.3 6.00 100 0 1.3

Detection: UV 254 nm

Detection: Quattro Micro, triple quadrupole

Ion source: ES+

Scan range: 90-1000 amu

Method: M12

Column: Sunfire, 3 × 30 mm, 2.5 μm (Waters) Gradient % Sol % Sol FlowTemp time [min] [H2O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.00 97 32.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 360

Method: M13

Column: Sunfire C18, 2.1 × 30 mm, 2.5 μm (Waters) Gradient % Sol % SolFlow Temp time [min] [H2O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.099 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5 60

9. PHARMACOLOGICAL TEST METHOD

Ussing Chamber: Mouse kidney M-1 cells were cultivated in DMEMcontaining 5% FCS and 5 μM dexamethasone for 10 to 12 days on polyestertranswell filters. Filters were inserted into a teflon-coated well-platewhich fit into the in-house ussing chamber system. Prior to measurementthe medium of M-1 cells was replaced with Caco-2 transport buffer(Invitrogen, Germany). During measurements, the Ussing chambertemperature was kept at 37° C. Short circuit currents (I_sc) weremeasured in the voltage-clamp mode using an in-house built amplifier(Boehringer Ingelheim, Biberach) with the software package Lab View fordata acquisition and analysis. The transepithelial electrical resistance(TEER) was determined by the application of voltage steps of ±5 mV every5 sec. Compounds were administered at a final concentration of 3 μM orat increasing concentrations (1-3-10 μM) to the apical solution. At theend of each experiment the amiloride sensitive I_SC was measured byadding 3 μM amiloride to the apical compartment. Results are expressedas IC50. Results are listed in tables 1 to 5 and further examples listedabove.

10. INDICATIONS

As has been found, the compounds of formula (I) are characterised bytheir wide range of applications in the therapeutic field. Particularmention should be made of those applications for which the compoundsaccording to the invention of formula (I) are preferably suited onaccount of their pharmaceutical efficacy as ENaC inhibitors. Examplesinclude respiratory diseases or complaints, or allergic diseases of theairways.

Particular mention should be made of the prevention and treatment ofdiseases of the airways and of the lung which are accompanied byincreased mucus production, inflammations and/or obstructive diseases ofthe airways. Examples include acute, allergic or chronic bronchitis,chronic obstructive pulmonary disease (COPD), coughing, pulmonaryemphysema, allergic or non-allergic rhinitis or sinusitis, chronicrhinitis or sinusitis, asthma, alveolitis, Farmer's disease,hyperreactive airways, infectious bronchitis or pneumonitis, pediatricasthma, bronchiectases, pulmonary fibrosis, ARDS (acute adultrespiratory distress syndrome), bronchial oedema, pulmonary oedema,bronchitis, pneumonia or interstitial pneumonia triggered by variouscauses, such as aspiration, inhalation of toxic gases, or bronchitis,pneumonia or interstitial pneumonia as a result of heart failure,irradiation, chemotherapy, cystic fibrosis or mucoviscidosis, oralpha1-antitrypsin deficiency.

Particularly preferably the present invention relates to the use ofcompounds of formula (I) for preparing a pharmaceutical composition forthe treatment of inflammatory or obstructive diseases of the upper andlower respiratory tract including the lungs, such as for exampleallergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis,COPD, chronic bronchitis, chronic sinusitis, asthma, particularly COPD,chronic bronchitis, cystic fibrosis and asthma.

It is most preferable to use the compounds of formula (I) for thetreatment of inflammatory and obstructive diseases such as COPD, chronicbronchitis, chronic sinusitis, asthma, cystic fibrosis, particularlyCOPD, chronic bronchitis and cystic fibrosis.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a pharmaceutically effective amount to bedelivered based upon patient's unique condition.

11. COMBINATIONS

The compounds of formula (I) may be used on their own or in conjunctionwith other active substances of (I) according to the invention. Ifdesired the compounds of formula (I) may also be used in combinationwith other pharmacologically active substances.

Therefore the invention further relates to medicament combinations whichpreferably contain, besides one or more compounds of formula (I), asfurther active substances, one or more compounds selected from among thecategories of further ENaC inhibitors, betamimetics, anticholinergics,corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors,dopamine agonists, H1-antihistamines, PAF-antagonists, MAP-kinaseinhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors,corrections of the cystic fibrosis transmembrane regulator (CFTR) andCFTR potentiators, or double or triple combinations thereof.

Examples of preferred betamimetics which may be mentioned includeAlbuterole, Arformoterole, Bambuterole, Bitolterole, Broxaterole,Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline,Ibuterole, Isoetharine, Isoprenaline, Levosalbutamole, Mabuterole,Meluadrine, Metaproterenole, Milveterol, Orciprenaline, Pirbuterole,Procaterole, Reproterole, Rimiterole, Ritodrine, Salmefamole,Salmeterole, Soterenole, Sulphonterole, Terbutaline, Tiaramide,Tolubuterole, Zinterole, Nolomirole, and

-   -   1-(2-chloro-4-hydroxyphenyl)-t-butylaminoethanole,    -   (−)-2-[7(S)-[2(R)-Hydroxy-2-(4-hydroxyphenyl)-ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamide        hydrochloride monohydrate,    -   3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulfonamide    -   5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one    -   4-Hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone    -   1-(2-Fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanole    -   1-[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanole    -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanole    -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanole    -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanole    -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanole    -   5-Hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one    -   1-(4-Amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanole    -   6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    -   6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid        ethylester)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    -   6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic        acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    -   8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    -   6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    -   6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    -   8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    -   8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    -   4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric        acid    -   8-{2-[2-(3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    -   1-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanole    -   N-[2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide    -   8-Hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one    -   8-Hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1        H-quinolin-2-one    -   5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one    -   [3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea    -   4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenole    -   3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide    -   3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulfonamide    -   4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenole    -   N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide    -   (R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenole    -   (R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenole    -   (R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenole    -   (R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenole    -   (R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one    -   (R,S)-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenole    -   4-(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol    -   (R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5|5-tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenole    -   (R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]formamide    -   (R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenole    -   (R,S)—N-[3-(1,1-Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]urea    -   3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)        phenyl]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione    -   (R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenole    -   5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one    -   4-((1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenole    -   (R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenole    -   (R,S)-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenole    -   (R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenole    -   3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide    -   N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide    -   7-[2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one        and        7-[(1R)-2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one

optionally in racemic form, as enantiomers, diastereomers or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

Examples of preferred anticholinergics which may be mentioned includeTiotropium salts, preferred the bromide salt, Oxitropium salts,preferred the bromide salt, Flutropium salts, preferred the bromidesalt, Ipratropium salts, preferred the bromide salt, Aclidinium salts,preferred the bromide salt, Glycopyrronium salts, preferred the bromidesalt, Trospium salts, preferred the chloride salt, Tolterodin. From theabove mentioned salts the pharmacologically active part is the cation,possible anions are chloride, bromide, iodide, sulfate, phosphate,methansulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate,oxalate, succinate, benzoate or p-toluenesulfonate. Further examples ofpreferred anticholinergics are selected from among

-   -   2,2-Diphenylpropionic acid tropenole ester-methobromide    -   2,2-Diphenylpropionic acid scopine ester-methobromide    -   2-Fluor-2,2-Diphenylacetic acid scopine ester-methobromide    -   2-Fluor-2,2-Diphenylacetic acid tropenole ester-methobromide    -   3,3′,4,4′-Tetrafluorbenzil acid tropenole ester-methobromide    -   3,3′,4,4′-Tetrafluorbenzil acid scopine ester-methobromide    -   4,4′-Difluorbenzil acid tropenole ester-methobromide    -   4,4′-Difluorbenzil acid scopine ester-methobromide    -   3,3′-Difluorbenzil acid tropenole ester-methobromide    -   3,3′-Difluorbenzil acid scopine ester-methobromide    -   9-Hydroxy-fluorene-9-carbon acid tropenole ester-methobromide    -   9-Fluor-fluorene-9-carbon acid tropenole ester-methobromide    -   9-Hydroxy-fluorene-9-carbon acid scopine ester-methobromide    -   9-Fluor-fluorene-9-carbon acid scopine ester methobromide    -   9-Methyl-fluorene-9-carbon acid tropenole estermethobromide    -   9-Methyl-fluorene-9-carbon acid scopine estermethobromide    -   Benzil acid cyclopropyl tropine ester-methobromide    -   2,2-Diphenylpropionic acid cyclopropyl tropine        ester-methobromide    -   9-Hydroxy-xanthene-9-carbon acid cyclopropyl tropine        ester-methobromide    -   9-Methyl-fluorene-9-carbon acid cyclopropyl tropine        ester-methobromide    -   9-Methyl-xanthene-9-carbon acid cyclopropyl tropine        ester-methobromide    -   9-Hydroxy-fluorene-9-carbon acid cyclopropyl tropine        ester-methobromide    -   4,4′-Difluorbenzil acid methylester cyclopropyl tropine        ester-methobromide    -   9-Hydroxy-xanthene-9-carbon acid tropenole ester-methobromide    -   9-Hydroxy-xanthene-9-carbon acid scopine ester methobromide    -   9-Methyl-xanthene-9-carbon acid tropenole ester-methobromide    -   9-Methyl-xanthene-9-carbon acid scopine estermethobromide    -   9-Ethyl-xanthene-9-carbon acid tropenole ester methobromide    -   9-Difluormethyl-xanthene-9-carbon acid tropenole        ester-methobromide    -   9-Hydroxymethyl-xanthene-9-carbon acid scopine ester        methobromide.

Examples of preferred corticosteroids which may be mentioned includeBeclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide,Deflazacorte, Dexamethasone, Etiprednole, Flunisolide, Fluticasone,Loteprednole, Mometasone, Prednisolone, Prednisone, Rofleponide,Triamcinolone, Tipredane, and

-   -   {20R-16alpha,17alpha-[butylidenebis(oxy)]-6alpha,9alpha-difluoro-11beta-hydroxy-17beta-(methylthio)androsta-4-en-3-one},    -   9-fluoro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione        21-cyclohexanecarboxylate 17-cyclopropanecarboxylate,    -   16,17-butylidene        dioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one    -   Flunisolide-21-[4′-(nitrooxymethyl) benzoate]    -   6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothion        acid (S)-fluoromethylester,    -   6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothion        acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, and    -   6alpha,9alpha-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylic        acid cyanomethyl ester

optionally in racemic form, as enantiomers, diastereomers or aspharmacologically acceptable salts, solvates or hydrates. Examples forpreferred salts and derivatives are alkali salts, i.e. sodium orpotassium salts, sulfobenzoates, phosphates, isonicotinates, acetates,dichloroacetates, propionates, dihydrogenphosphates, palmitates,pivalates or furoates.

Examples of preferred PDE4-inhibtors which may be mentioned includeEnprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilaste),Tofimilaste, Pumafentrine, Lirimilaste, Apremilaste, Arofylline,Atizorame, Oglemilastum, Tetomilaste and

-   -   5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline    -   5-[N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline    -   N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]glyoxyl        acid amide),        9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine        4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine,    -   N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-Pyridinecarboxamide,    -   4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone,    -   2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-Phthalazinone,    -   (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine,    -   beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide,    -   9-ethyl-2-methoxy-7-methyl-5-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one    -   5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]        (3S,5S)-2-piperidinone,    -   4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-Benzenemethanol    -   N-(3,5-Dichloro-1-oxo-pyridine-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide    -   (−)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide    -   (R)-(+)-1-(4-Bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone    -   3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N′—[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone    -   cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carbon        acid]    -   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one    -   cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]    -   (R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate    -   (S)-(−)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate    -   9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine    -   9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine

optionally in racemic form, as enantiomers, diastereomeres or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

-   -   Examples of preferred LTD4-antagonists which may be mentioned        include Montelukast, Pranlukast, Zafirlukast, Masikulast ,        L-733321 (see compound 2ab of D. Guay et al, Bioorg. Med. Chem.        Lett. 8 (1998) 453-458) and        (E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazole-5-yl)-4H-1-benzopyran-4-one        (MEN-91507)    -   4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyric        acid (MN-001)    -   1-(((R)-(3-(2-(6,7-Difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic        acid,    -   1-(((1(R)-3(3-(2-(2,3-Dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane        acetic acid    -   [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic        acid

optionally in racemic form, as enantiomers, diastereomers or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate. Further examples for optionally preferredsalts and derivatives are alkali salts, i.e. sodium or potassium salts,sulfobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogenphosphates, palmitates, pivalates or furoates.

Examples of preferred EGFR-inhibitors which may be mentioned includeCetuximab, Trastuzumab, Panitumumab Gefitinib, Canertinib, Erlotinib,Mab ICR-62 and

-   -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopentyloxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine    -   3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline    -   4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline    -   4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-butene-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholine-411)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidine-4-yloxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulfonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methansulfonylamino-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(piperidine-1-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy        quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)sulfonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-ethoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidine-1-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholine-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidine-1-yl)ethyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-chinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-(piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-methoxy-quinazoline    -   4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-ethyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazoline    -   4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-methoxy-quinazoline

optionally in racemic form, as enantiomers, diastereomeres or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

Examples of preferred dopamine antagonists which may be mentionedinclude Bromocriptine, Cabergoline, Alpha-Dihydroergocryptine, Lisuride,Pergolide, Pramipexole, Roxindole, Ropinirole, Talipexole, Terguride andViozane, optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Preferred are salts selected from the group consisting of hydrochloride,hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Examples of preferred antiallergic agents which may be mentioned includeEpinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine,Loratadine, Mizolastine, Ketotifene, Emedastine, Dimetindene,Clemastine, Bamipine, Cexchlorpheniramine, Pheniramine, Doxylamine,Chlorphenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine,Ebastine, Olopatadine, Desloratidine and Meclozine, optionally inracemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Preferred are salts selected from the group consisting of hydrochloride,hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred PAF antagonists which may be mentioned includeLexipafante and

-   -   4-(2-Chlorphenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanone-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine    -   6-(2-Chlorphenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

optionally in racemic form, as enantiomers, diastereomers or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate undhydro-p-toluenesulfonate.

Examples of preferred MAP kinase inhibitors which may be mentionedinclude

-   -   Bentamapimod (AS-602801)    -   Doramapimod (BIRB-796),    -   5-Carbamoylindole (SD-169),    -   6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridine        carboxamide (VX-702),    -   alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazole        acetonitrile (AS-601245),    -   9,12-Epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-Carboxylic        acid (CEP-1347),    -   4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazole-4-yl]-pyrimidine        (SC-409),

optionally in racemic form, as enantiomers, diastereomers or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate undhydro-p-toluenesulfonate.

Examples of preferred MRP4 inhibitors which may be mentioned includeN-Acetyl-dinitrophenyl-Cysteine, cGMP, Cholate, Diclofenac,Dehydroepiandrosterone 3-glucuronide, Dehydroepiandrosterone 3-sulfate,Dilazep, Dinitrophenyl-S-glutathione, Estradiol 17-beta-glucuronide,Estradiol 3,17-disulfate, Estradiol 3-glucuronide, Estradiol 3-sulfate,Estrone 3-sulfate, Flurbiprofen, Folate, N5-formyl-tetrahydrofolate,Glycocholate, Glycolithocholic acid sulfate, Ibuprofen, Indomethacin,Indoprofen, Ketoprofen, Lithocholic acid sulfate, Methotrexate,(E)-3-[[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid alpha-Naphthyl-beta-D-glucuronide, Nitrobenzyl mercaptopurineriboside, Probenecid, Valspodar , Sildenafil, Sulfinpyrazone,Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate,Taurolithocholate, Taurolithocholic acid sulfate, Topotecan, Trequinsin,Zaprinast and Dipyridamol, optionally in racemic form, as enantiomers,diastereomeres or as pharmacologically acceptable salts, solvates orhydrates.

Preferred are salts selected from the group consisting of hydrochloride,hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Examples of preferred iNOS-Inhibitors which may be mentioned includeS-(2-Aminoethyl)isothio-urea, Aminoguanidine, 2-Aminomethylpyridine,5,6-dihydro-6-methyl-4H-1,3-thiazine-2-amine (AMT), L-Canavanin,2-Iminopiperidine, S-Isopropylisothiourea, S-Methylisothiourea,S-Ethylisothiourea, S-Methylthiocitrulline, S-Ethylthiocitrulline, L-NA(N^(ω)-Nitro-L-arginin), L-NAME (N^(ω)-Nitro-L-argininmethylester),L-NMMA (N^(ω)-Monomethyl-L-arginin), L-NIO(N^(ω)-Iminoethyl-L-ornithin), L-NIL (N^(ω)-iminoethyl-lysin),(S)-6-Acetimidoylamino-2-amino-hexanoic acid (1H-tetrazole-5-yl)-amideN-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide,(S)-4-(2-acetimidoylamino-ethylsulfanyl)-2-amino-buturic acid,2-[2-(4-Methoxy-pyridine-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine,2-((R)-3-amino-1-phenyl-propoxy)-4-chlor-5-fluorbenzonitrile,2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile,2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-4-chlor-benzonitrile,2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-5-chlor-benzonitrile,(2S,4R)-2-amino-4-(2-chlor-5-trifluoromethyl-phenylsulfanyl)-4-thiazole-5-yl-butane-1-ol,2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-5-chlor-nicotinonitrile,4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulfanyl)-6-methoxy-nicotinonitrileand substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine as for instance1S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-3-ylamin(4R,5R)-5-Ethyl-4-methyl-thiazolidine-2-ylideneamine,(1S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-3-ylamin,(4R,5R)-5-Ethyl-4-methyl-thiazolidine-2-ylideneamine,(4R,5R)-5-Ethyl-4-methyl-selenazolidine-2-ylideneamine,4-Aminotetrahydrobiopterine,(E)-3-(4-Chlor-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluormethyl-pyrimidine-4-yloxy)-piperidine-1-yl]-ethylcarbamoyl}-2-pyridine-2-yl-ethyl)-acrylamide,3-(2,4-Difluor-phenyl)-6-[2-(4-imidazole-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine,3-{[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazole-1-yl-pyrimidine-4-yl)-piperazine-1-carbonacid methylester,(R)-1-(2-imidazole-1-yl-6-methyl-pyrimidine-4-yl)-pyrrolidine-2-carbonacid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide, optionally in racemic form,as enantiomers, diastereomers or as pharmacologically acceptable salts,solvates or hydrates. Preferred are salts selected from the groupconsisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate,hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Further examples of preferred iNOS-Inhibitors which may be mentionedinclude antisense-Oligonucleotide, especially thoseantisense-Oligonucleotide bindung iNOS-coding nucleinic acids, examplestherefore are disclosed in WO 01/52902.

Examples of preferred SYK-inhibitors which may be mentioned include

-   -   2-[(2-aminoethyl)amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide;    -   2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidine-5-yl]amino]-3-pyridinecarboxamide;    -   6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one;    -   N-[3-bromo-7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   7-(4-methoxyphenyl)-N-methyl-1,6-naphthyridine-5-amine;    -   N-[7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(2-thienyl)-1,6-naphthyridine-5-yl-1,3-propanediamine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-ethanediamine;    -   N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(4-methoxyphenyl)-3-phenyl-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-(7-phenyl-1,6-naphthyridine-5-yl)-1,3-propanediamine;    -   N-[7-(3-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(3-chlorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[3-(trifluoromethoxy)phenyl]-1,6-naphthyridine-5yl]-1,3-propanediamine;    -   N-[7-(4-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(4-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(4-chlorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(4′-methyl[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-1,3-propanediamine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(4-bromophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(4-methylphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(methylthio)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(1-methylethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   7-[4-(dimethylamino)phenyl]-N-methyl-1,6-naphthyridine-5-amine;    -   7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1,6-naphthyridine-5-amine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,5-pentanediamine;    -   3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]oxy]-1-propanole;    -   4-[5-(4-aminobutoxy)-1,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine;    -   4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-1-butanole;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N-methyl-1,3-propanediamine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N′-methyl-1,3-propanediamine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N,N′-dimethyl-1,3-propanediamine;    -   1-amino-3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-2,2-dimethyl-1,3-propanediamine;    -   7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1,6-naphthyridine-5-amine;    -   N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-amine;    -   N-[7-[6-(dimethylamino)[1,1′-biphenyl]-3-yl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[3-chloro-4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(diethylamino)phenyl]-3-methyl-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(3′-fluoro[1,1′-biphenyl]-3-yl)-1,6-naphthyridine-5-yl]-1,2-ethanediamin,    -   N-[7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,6-naphthyridine-1,3-propanediamine;    -   N,N′-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine;    -   N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1,6-naphthyridine-5-yl]-1,6-naphthyridine-1,3-propanediamine;    -   N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine;    -   N-[7-(2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(3,4-dimethylphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   1-amino-3-[[7-(2-naphthalenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   1-amino-3-[[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   1-amino-3-[[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   1-amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   N-[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-2,2-dimethyl-1,3-propanediamine;    -   1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-2-propanole;    -   2-[[2-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]ethyl]thio]-ethanole;    -   7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1,6-naphthyridine-5-amine;    -   7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-1,6-naphthyridine-5-amine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-cyclohexane        diamine;    -   N,N-dimethyl-4-[5-(1-piperazinyl)-1,6-naphthyridine-7-yl]-benzenamine;    -   4-[5-(2-methoxyethoxy)-1,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine;    -   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-4-piperidinole;    -   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-3-pyrrolidinole;    -   7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1,6-naphthyridine-5-amine;    -   7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazole-1-yl)propyl]-1,6-naphthyridine-5-amine;    -   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-4-piperidine        carboxamide;    -   1-[3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]propyl]-2-pyrrolidinone;    -   N-[3′-[5-[(3-aminopropyl)amino]-1,6-naphthyridine-7-yl][1,1′-biphenyl]-3-yl]-acetamide;    -   N-[7-(4′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[4′-[5-[(3-aminopropyl)amino]-1,6-naphthyridine-7-yl][1,1′-biphenyl]-3-yl]-acetamide;    -   N-[7-[4-(1,3-benzodioxol-5-yl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(2-thienyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(3-pyridinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(1,3-benzodioxol-5-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridine-5-amine;    -   3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]methylamino]-propanenitrile;    -   7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1,6-naphthyridine-5-amine;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-cyclohexanediamin,    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-Cyclohexanediamine,        (1R,2S)-rel-.    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-benzene        dimethanamine;    -   N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamine;    -   N-[7-[3′,5′-bis(trifluoromethyl)[1,1′-biphenyl]-4-yl]-1,6-naphthyridine-5-yl]-,3-propanediamine;    -   N-[7-(3′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(3′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]oxy]-1-butanole;    -   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;    -   7-[4-(dimethylamino)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-1,6-naphthyridine-5-amine;    -   N-[7-[3-bromo-4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(1-methyl-1H-indole-5-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[3-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-(3-bromo-4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;    -   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;    -   N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;    -   N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;    -   N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;    -   4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]oxy]-cyclohexanole;    -   N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;    -   N,N-dimethyl-4-[5-(4-methyl-1-piperazinyl)-1,6-naphthyridine-7-yl]-benzenamine;    -   4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]oxy]-cyclohexanole;    -   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamin;    -   [3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridine-2-yl]amino]propyl]-carbamic        acid-1,1-dimethylethyl ester,

optionally in racemic form, as enantiomers, diastereomers or aspharmacologically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

Examples of preferred cystic fibrosis transmembrane regulators (CFTR)and CFTR potentiators which may be mentioned include, preferably VX-770and VX-809

12. FORMULATIONS

Suitable forms for administration are for example inhalable powders oraerosols. The content of the pharmaceutically effective compound(s) ineach case should be in the range from 0.2 to 50 wt %, preferably 5 to 25wt. % of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

Administered by inhalation the active substance combination may be givenas a powder, as an aqueous or aqueous-ethanolic solution or using apropellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised inthat they contain one or more compounds of (I) according to thepreferred embodiments above.

It is also preferred if the compounds of formula (I) are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula (I) have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also include concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula (I) are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain a compound of formula (I) dissolved in thepropellant gas or in dispersed form. The propellant gases which may beused to prepare the inhalation aerosols according to the invention areknown from the prior art. Suitable propellant gases are selected fromamong hydrocarbons such as n-propane, n-butane or isobutane andhalohydrocarbons such as preferably fluorinated derivatives of methane,ethane, propane, butane, cyclopropane or cyclobutane. The propellantgases mentioned above may be used on their own or in mixtures thereof.Particularly preferred propellant gases are fluorinated alkanederivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. Thepropellant-driven inhalation aerosols used within the scope of the useaccording to the invention may also contain other ingredients such asco-solvents, stabilisers, surfactants, antioxidants, lubricants and pHadjusters. All these ingredients are known in the art.

Propellant-Free Inhalable Solutions

The compounds of formula (I) according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulfuric acids.It is also possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may also be used, particularly in the caseof acids which have other properties in addition to their acidifyingqualities, e.g. as flavourings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art.

For the treatment forms described above, ready-to-use packs of amedicament for the treatment of respiratory complaints are provided,containing an enclosed description including for example the wordsrespiratory disease, COPD or asthma, a compound according to theinvention and one or more combination partners selected from thosedescribed above.

The following example illustrates the present invention withoutrestricting its scope:

Capsule for Powder Inhalation

1 capsule contains:

active substance 0.5 mg lactose for inhalation 5.0 mg 5.5 mg

Preparation:

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg).

weight of capsule: 55.5 mg

size of capsule=3

1. A method for the treatment of cystic fibrosis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound selected from the group consisting of:

or a pharmacologically acceptable acid addition salt of any one of theabove compounds.
 2. The method according to claim 1, wherein thecompound is

or a pharmacologically acceptable salt thereof.
 3. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 4. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 5. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 6. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 7. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 8. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 9. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 10. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 11. The method accordingto claim 1, wherein the compound is

or a pharmacologically acceptable salt thereof.
 12. A method for thetreatment of chronic obstructive pulmonary disease (COPD) comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound selected from the group consisting of:

or a pharmacologically acceptable acid addition salt of any one of theabove compounds.
 13. The method according to claim 12, wherein thecompound is

or a pharmacologically acceptable salt thereof.
 14. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 15. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 16. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 17. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 18. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 19. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 20. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 21. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.
 22. The method accordingto claim 12, wherein the compound is

or a pharmacologically acceptable salt thereof.